Skip to main content

Full text of "The dispensatory of the United States of America"

See other formats


Synopsis  of  Arrangement 
United  States  Dispensatory 


PART  ONE:  Drugs  recognized  by  The  United  States 
Pharmacopeia,  British  Pharmacopoeia,  International 
Pharmacopoeia,  or  The  National  Formulary. 

Individual  monographs  are  arranged  alphabetically  according  to  the  Eng- 
lish title,  with  information  for  each  drug  in  general  following  the  order: 

•  Official  Tides  and  Synonyms 

•  Official  Definition 

•  Unofficial  Synonyms,  Foreign  Language  Tides    (official 

titles  appear  in  bold-face  type) ,  Trade-names  and  Trade- 
marks (name  of  manufacturer  indicated  parenthetically) 

•  Source  or  Manufacturing  Process;  History 

•  Official  Description;  Tests 

•  Assay  Methods 

•  Constituents 

•  Adulterants 

•  Therapeutic  Actions  and  Uses 

•  Toxicology 

•  Dosage 

•  Storage  Requirements 

•  Official  Preparations 

•  Usual  Sizes  (for  dosage  forms) 

PART  TWO:  Drugs  not  official  in  The  United  States 

Pharmacopeia,  British  Pharmacopoeia,  International 
Pharmacopoeia,  or  The  National  Formulary. 

Individual  monographs  are  arranged  alphabetically,  with 
information  for  each  drug  following  the  order  listed  above. 

PART  THREE :  Veterinary  Uses  and  Doses  of  Drugs 

COMPLETE  INDEX 


Table  of  Metric  Doses 
with  Approximate  Apothecary  Equivalents 


The  approximate  dose  equivalents  in  the  following  table  represent  the  quantities  usually  prescribed,  under 
identical  conditions,  by  physicians  trained,  respectively,  in  the  metric  or  in  the  apothecary  system  of  weights 
and  measures.  In  labeling  dosage  forms  in  both  the  metric  and  the  apothecary  systems,  if  one  is  the  approxi- 
mate equivalent  of  the  other,  the  approximate  figure  shall  be  enclosed  in  parentheses. 

When  prepared  dosage  forms  such  as  tablets,  capsules,  pills,  etc.,  are  prescribed  in  the  metric  system,  the 
pharmacist  may  dispense  the  corresponding  approximate  equivalent  in  the  apothecary  system,  and  vice 
versa,  as  indicated  in  the  following  table. 

Caution — For  the  conversion  of  specific  quantities  in  a  prescription  which  requires  compounding,  or  in 
converting  a  pharmaceutical  formula  from  one  system  of  weights  or  measures  to  the  other,  exact  equivalents 
must  be  used. 


Liquid  Measure 

Liquid  Measure 

Approximate 

Approximate 

Apothecary 

Apothecary 

Metric 

Equivalents 

Metric 

Equivalents 

1000  ml. 

1      quart 

3 

ml. 

45 

minims 

750  ml. 

1  Vz  pints 

2 

ml. 

30 

minims 

500  ml. 

1      pint 

1 

ml. 

15 

minims 

250  ml. 

8     fluidounces 

0.75  ml. 

12 

minims 

200  ml. 

7     fluidounces 

0.6 

ml. 

10 

minims 

100  ml. 

3V4  fluidounces 

0.5 

ml. 

8 

minims 

50  ml. 

1%  fluidounces 

0.3 

ml. 

5 

minims 

30  ml. 

1      fluidounce 

0.25  ml. 

4 

minims 

15  ml. 

4     fluidrachms 

0.2 

ml. 

3 

minims 

10  ml. 

254  fluidrachms 

0.1 

ml. 

V/z 

minims 

8  ml. 

2     fluidrachms 

0.06  ml. 

1 

minim 

5  ml. 

1 54  fluidrachms 

0.05  ml. 

% 

minim 

4  ml. 

1      fluidrachm 

0.03  ml. 

Vz 

minim 

Weight 

Weight 

Approximate 

Approximate 

Apothecary 

Apothecary 

Metric 

Equivalents 

Metric 

Equivalents 

30     Gm. 

1      ounce 

30 

mg. 

y2 

grain 

15     Gm. 

4     drachms 

25 

mg. 

% 

grain 

10    Gm. 

2/4  drachms 

20 

mg. 

Vz 

grain 

7.5  Gm. 

2      drachms 

15 

mg. 

V* 

grain 

6    Gm. 

90     grains 

12 

mg. 

% 

grain 

5    Gm. 

75     grains 

10 

mg. 

% 

grain 

4    Gm. 

60     grains  (1  drachm) 

8 

mg. 

y* 

grain 

3    Gm. 

45     grains 

6 

mg. 

%0 

grain 

2    Gm. 

30     grains  {Vz  drachm) 

5 

mg. 

VVL 

grain 

1.5  Gm. 

22     grains 

4 

mg. 

%5 

grain 

1     Gm. 

15     grains 

3 

mg. 

Y20 

grain 

750    mg. 

12     grains 

2 

mg. 

%0 

grain 

600    mg. 

10     grains 

1.5 

mg. 

y40 

grain 

500    mg. 

7/4  grains 

1.2 

mg. 

Vm 

grain 

400    mg. 

6     grains 

1 

mg. 

Yeo 

grain 

300    mg. 

5     grains 

800 

meg. 

Yso 

grain 

250    mg. 

4     grains 

600 

meg. 

Yioo 

grain 

200    mg. 

3     grains 

500 

meg. 

Yl20 

grain 

150    mg. 

254  grains 

400 

meg. 

M50  grain 

120    mg. 

2     grains 

300 

meg. 

Y200 

grain 

100    mg. 

1  Vz  grains 

250 

meg. 

%50 

grain 

75    mg. 

1 54  grains 

200 

meg. 

%00 

grain 

60    mg. 

1      grain 

150 

meg. 

■54oo 

grain 

50    mg. 

%  grain 

120 

meg. 

Yooo 

grain 

40    mg. 

Vi  grain 

100 

meg. 

%00 

grain 

Note:  A  cubic  centimeter  (cc.)  is  the  approximate  equivalent  of  a  milliliter  (ml.). 

The  above  approximate  dose  equivalents  have  been  adopted  by  the  latest  Pharmacopeia,  National  Formulary,  and 
New  and  Non-official  Remedies,  and  these  dose  equivalents  have  the  approval  of  the  Federal  Food  and  Drug 
Administration. 


THE   DISPENSATORY 

OF   THE    UNITED   STATES 
OF   AMERICA    ** 


NOV  16198* 

THfc  CORNER  PHARMACY 

NOV  16  195f 


Contributors 


Howard  N.  Baier,  b.s.,  m.d.,  m.s. 

Associate  in  Medicine  and  Physiology,  Temple  Uni- 
versity School  of  Medicine  and  Hospital. 

Mahlon  Z.  Bierly,  Jr.,  b.s.,  m.d. 
Assistant  Physician,  Visiting  Staff,  Children's  Hospi- 
tal of  Philadelphia;  Assistant  Pediatrician  to   OPD, 
Bryn  Mawr  Hospital. 

Eleanor  E.  Buckley,  b.s. 

Staff  Writer,  Medical  Department  Wyeth  Laboratories, 
Inc. 

Peter  T.  Cassalia,  b.s.,  d.d.s.,  m.s. 

Chief   of   Oral  Surgery,    Northeastern   Hospital   and 
Lower  Bucks  County  Hospital. 

Dean  A.  Collins,  a.b.,  a.m.,  ph.d.,  m.d. 

Professor  and  Head  of  the  Department  of  Pharma- 
cology, Temple  University  School  of  Medicine. 

David  W.  Crjsman,  b.s.,  v.m.d. 

Assistant  Professor  of  Microbiology,  School  of  Veteri- 
nary Medicine,  University  of  Pennsylvania. 

Elmer  H.  Funk,  Jr.,  b.s.,  m.d. 

Assistant    in    Aiedicine,    Jefferson    Medical    College: 

Assistant  Cardiologist  to   Out-Patients,   Pennsylvania 

Hospital. 

Joan  H.  Long  Gault,  b.s.,  m.d.,  m.s. 

Instructor  in  Medicine,  Temple  University  School  of 
Medicine. 

Alfonso  R.  Gennaro,  b.s.,  m.s. 

Instructor  in  Chemistry,  Philadelphia  College  of  Phar- 
macy and  Science. 


Elizabeth  W.  Johnson,  b.s.,  m.s. 

Librarian,    Philadelphia    College    of    Pharmacy 
Science. 

Lawrence  R.  Mallery,  Jr. 

Medical  Writer,  Gray  &  Rogers,  Philadelphia 


and 


John  E.  Martin,  v.m.d. 

Assistant  Professor  of  Physiology  and  Pharmacology, 
School  of  Veterinary  Medicine  and  Graduate  School  of 
Medicine,  University  of  Pennsylvania. 

Morton  J.  Oppenheimer,  a.b.,  m.ed.,  m.d. 

Professor  and  Head  of  the  Department  of  Physiology, 
Temple  University  School  of  Medicine  and  Hospital. 

Edward  F.  Roberts,  a.b.,  ph.d.,  m.d. 

Director  of  Clinical  Investigation,  Wyeth  Labora- 
tories, Inc. 

Bruce  S.  Roxby,  b.s.,  m.d.,  m.s. 

Instructor  in  Medicine,  Temple  University  School  of 
Medicine  and  Hospital;  Director  of  Health  Service, 
Temple  University. 

John  B.  Roxby,  Jr.,  b.a.,  m.a.,  m.d. 

Associate  in  Dermatology,  Temple  University  School 
of  Medicine  and  Hospital;  Dermatologist,  Chestnut 
Hill  Hospital  and  Northern  Division,  Philadelphia 
General  Hospital. 

Joseph  Seifter,  a.b.,  ph.d.,  m.d. 

Director,  Wyeth  Institute  for  Medical  Research;  Lec- 
turer in  Pharmacology,  Graduate  School  of  Medicine, 
University  of  Pennsylvania. 

Daniel  L.  Shaw,  Jr.,  b.s.,  m.d. 

Director  of  Clinical  Research,  Wyeth  Laboratories, 
Inc. ;  Instructor  in  Medicine,  Jefferson  Medical  College. 

Charles  R.  Shuman,  b.a.,  m.d.,  m.s. 

Associate  in  Medicine,  Temple  University  School  of 
Medicine  and  Hospital;  Consultant  in  Metabolic  Dis- 
ease, Philadelphia  Veterans  Administration  Hospital. 

Chris  J.  D.  Zarafonetis,  b.a.,  m.d.,  m.s. 

Associate  Professor  of  Medicine,  Temple  University 
School  of  Medicine  and  Hospital ;  Chief,  Hematology 
Division,  Temple  University  Hospital. 


THE  DISPENSATORY 

OF   THE   UNITED  STATES 
OF  AMERICA       *•>       25th  Edition 

ARTHUR  OSOL,  Ph.G.,  B.S.,  M.S.,  Ph.D. 

PROFESSOR  OF  CHEMISTRY  AND  DIRECTOR  OF   THE  DEPARTMENT  AND  SCHOOL  OF  CHEMISTRY,   PHILADELPHIA  COLLEGE 
OF    PHARMACY    AND    SCIENCE;    MEMBER    OF    THE    COMMITTEE    OF    REVISION    OF    THE    UNITED    STATES    PHARMACOPEIA 

GEORGE  E.  FARRAR,  Jr.,  B.S.,  M.D.,  F.A.C.P. 

MEDICAL   DIRECTOR,    WYETH    LABORATORIES,    INC.;    ASSOCIATE    PROFESSOR   OF    MEDICINE,    TEMPLE    UNIVERSITY   SCHOOL 
OF    MEDICINE    AND    HOSPITAL;    MEMBER    OF    THE    COMMITTEE    OF    REVISION    OF    THE    UNITED    STATES    PHARMACOPEIA 

WITH 
KARL  H.  BEYER,  Jr.,  b.s.,  ph.d.,  m.d.  DAVID  K.  DETWEILER,  v.m.d.,  m.s. 

LECTURER  IN  PHARMACOLOGY,  GRADUATE  SCHOOL  OF   MEDICINE,  ASSOCIATE    PROFESSOR  OF  VETERINARY  PHARMACOLOGY,   SCHOOL 

UNIVERSITY      OF      PENNSYLVANIA,      AND      TEMPLE      UNIVERSITY  OF    VETERINARY     MEDICINE,     GRADUATE    SCHOOL     OF    ARTS    AND 

SCHOOL     OF     MEDICINE;     ASSISTANT     DIRECTOR     OF     RESEARCH,  SCIENCES,    AND   THE    GRADUATE    SCHOOL   OF    MEDICINE,    UNIVER- 
SHARP   &  DOHME   DIVISION,    MERCK  St  CO.,    INC.  SITY  OF  PENNSYLVANIA 

JOHN  H.  BROWN,  v.m.d.  ROBERTSON  PRATT,  a.b.,  ph.d. 

PRODUCTION     MANAGER,     MARIETTA     BIOLOGICAL     LABORATORY,  PROFESSOR  OF  PHARMACOGNOSY  AND  ANTIBIOTICS,    UNIVERSITY 

WYETH   LABORATORIES,    INC.  OF  CALIFORNIA  COLLEGE  OF  PHARMACY 

HEBER  W.  YOUNGKEN,  ph.m.,  ph.d.,  sc.d. 

RESEARCH  PROFESSOR  OF   PHARMACOGNOSY  AND  BOTANY,   MASSA- 
CHUSETTS COLLEGE  OF  PHARMACY;  MEMBER  OF  THE  COMMITTEE 
OF    REVISION    OF    THE    UNITED   STATES    PHARMACOPEIA. 

Editor  Emeritus 
HORATIO  C.  WOOD,  Jr.,  M.D.,  Ph.M. 

PROFESSOR  EMERITUS  OF  PHARMACOLOGY,   PHILADELPHIA  COLLEGE  OF  PHARMACY  AND  SCIENCE; 
EMERITUS  PROFESSOR,   GRADUATE  SCHOOL  OF   MEDICINE,   UNIVERSITY  OF  PENNSYLVANIA 


Based  on  the  Fifteenth  Revision  of  The  United  States  Pharmacopeia,  the  Tenth 

Edition  of  The  National  Formulary,  The  British  Pharmacopoeia,  1953,  the  First 

Edition  of  the  International  Pharmacopoeia,  Volumes  I  and  11 


Philadelphia  ^|[jigg|^  Montreal 

J.  B.  LIPPINCOTT  COMPANY 


THE    DISPENSATORY    OF   THE    UNITED    STATES   OF    AMERICA 

\th  Edition 


25' 


Copyright  1955  by  J.  B.  LIPPINCOTT  COMPANY 
©  1955  by  J.  B.  LIPPINCOTT  COMPANY 


Entered,  according  to  Act  of  Congress,  in  the  year  1877, 

By  George  B.  Wood,  m.d., 
In  the  Office  of  the  Librarian  of  Congress  at  Washington 


Copyright,  1888,  1894,  1899,  1907,  by  H.  C.  Wood,  M.D. 


,  Copyright,  1918,  1926,  1937,  1943,  by  H.  C.  Wood,  Jr.,  m.d. 


Copyright,  1947,  1950,  by  J.  B.  LiPPiNCOTT  Company 


The  use  in  this  volume  of  certain  portions  of  the  text  of  the  United  States  Pharmacopeia,  Fifteenth 
Revision,  official  December  15,  1955,  is  by  virtue  of  permission  received  from  the  Board  of  Trustees  of  the 
United  States  Pharmacopceial  Convention.  The  said  Board  of  Trustees  is  not  responsible  for  any  inaccuracy 
of  quotation  nor  for  any  errors  in  the  statement  of  quantities  or  percentage  strengths. 

Permission  to  use  for  comment  parts  of  the  text  of  the  National  Formulary,  Tenth  Edition,  in  this  volume 
has  been  granted  by  the  Committee  on  Publications  by  authority  of  the  Council  of  the  American  Pharmaceutical 
Association. 


Distributed  in  Great  Britain  by 

Pitman  Medical  Publishing  Co.,  Limited 

London 


Library  of  Congress 

Catalog  Card  Number 

7-31327 


Printed  in  the  United  States  of  America 


Historical  Title  Page 


Editors 

First  Edition  (1833)  to  Eleventh  Edition  (1858) 
GEORGE  B.  WOOD  and  FRANKLIN  BACHE 


Twelfth  Edition  (1865)  and  Thirteenth  Edition  (1870) 
GEORGE  B.  WOOD 


Fourteenth  Edition  (1877) 
GEORGE  B.  WOOD  and  HORATIO  C.  WOOD 


Fifteenth  Edition  (1883)  to  Nineteenth  Edition  (1907) 
HORATIO  C  WOOD,  JOSEPH  P.  REMINGTON  and  SAMUEL  P.  SADTLER 


Twentieth  Edition  (1918) 
JOSEPH  P.  REMINGTON  and  HORATIO  C.  WOOD,  Jr. 


Twenty-first  Edition  (1926)  and  Twenty-second  Edition  (1937) 
HORATIO  C  WOOD,  Jr.,  and  CHARLES  H.  LaWALL 


Twenty-third  Edition  (1943) 
HORATIO  C  WOOD,  Jr.,  and  ARTHUR  OSOL 


Twenty-fourth  Edition  (1947) 
ARTHUR  OSOL  and  GEORGE  E.  FARRAR,  Jr. 


The  following  have  also  been  employed  as  Associate  Editors  in  the  preparation  of  the 
various  editions: 


WILLIAM  PROCTER 
ROBERT  BRIDGES 
HENRY  H.  RUSBY 
HENRY  KRAEMER 
ALBERT  B.  LYONS 
JOHN  F.  ANDERSON 


LOUIS  GERSHENFELD 
HEBER  W.  YOUNGKEN 
IVOR  GRIFFITH 
ARTHUR  OSOL 
E.  EMERSON  LEUALLEN 
WILLARD  F.  VERWEY 


Publishers 


First  to  Eighth  Edition 
GRIGG  &  ELLIOT 

Ninth  to  Eleventh  Edition 
LIPPINCOTT,  GRAMBO  &  CO. 


Twelfth  to  Fourteenth  Edition 
J.  B.  LIPPINCOTT  &  CO. 

Fifteenth  to  Twenty-fourth  Edition 
J.  B.  LIPPINCOTT  COMPANY 


Preface 


This  new  edition  of  the  UNITED  STATES 
DISPENSATORY  documents  the  progress  of 
knowledge  concerning  medicinal  agents  in  an  era 
of  unprecedented  development  and  expansion  in 
this  field  of  medical  service.  In  no  period  of  the 
long  history  of  this  book  has  so  much  new  infor- 
mation been  incorporated  and  so  extensive  a  re- 
vision of  older  information  been  consummated. 
This  is  in  large  measure  attributable  to  the  fact, 
on  the  one  hand,  that  many  medicinal  substances 
have  hardly  reached  therapeutic  maturity  before 
they  are  replaced  by  even  safer  and  more  effective 
drugs  and,  on  the  other,  to  the  finding  of  new 
uses  for  older  drugs  as  research  has  disclosed 
hitherto  unrecognized  therapeutic  applications  or 
led  to  the  isolation,  in  the  case  of  drugs  of  natural 
origin,  of  potent  and  therapeutically  effective 
constituents. 

The  total  of  new  admissions  to  the  United 
States  Pharmacopeia,  the  National  Formulary,  the 
British  Pharmacopoeia,  and  the  two  volumes  of 
the  International  Pharmacopoeia,  together  with 
the  new  non-official  drugs  described  for  the  first 
time  in  this  edition  of  the  DISPENSATORY, 
exceeds  500. 

While  maintaining  the  traditional  treatment  of 
drugs  according  to  alphabetic  arrangement — which 
has  many  advantages — a  feature  of  this  edition 
of  the  DISPENSATORY  is  the  inclusion  of  many 
new  general  survey  articles  on  pharmacological 
classes  of  drugs.  Thus,  there  appear  in  Part  Two 
articles  on  the  following:  Adrenergic  Blocking 
Agents,  Anticoagulant  Drugs,  Antihistamines,  Anti- 
metabolites, Barbiturates,  Curarimimetic  Agents 
and  their  Antagonists,  Ganglionic  Blocking  Agents, 
Local  Anesthetic  Agents,  Nephrotropic  Agents, 
Parasympathetic  Blocking  Agents,  Parasympa- 
thomimetic Agents  and  Cholinesterase  Inhibitors, 
and  Skeletal  Antispasmodic  Compounds.  These 
articles  provide  the  basis  for  comparing  drugs  in 
the  several  categories  indicated;  also,  a  correla- 
tion between  pharmacological  action  and  chemical 
structure  is  thereby  often  possible,  especially  since 
these  general  articles  are  amply  illustrated  with 
structural  formulas.  Certain  other  general  articles 
have  been  completely  rewritten  as,  for  example, 
that  on  Antibiotics,  also  in  Part  Two.  The  estab- 
lished uses  of  radioisotopes  in  medicine  have 
naturally  necessitated  addition  of  a  general 
article  on  this  subject,  in  addition  to  a  specific 
article  on  the  official  Sodium  Radio-iodide  (I131) 
Solution  and  innumerable  references  throughout 
the  book  to  specific  uses  of  radioisotopes  as  tracer 
substances. 


As  in  preceding  editions  of  the  DISPENSA- 
TORY, all  articles  are  amply  documented  by 
original  literature  references  in  order  to  establish 
the  authority  for  the  information  that  is  provided 
and  to  facilitate  further  search  of  the  literature 
when  this  is  required.  In  this  connection  it  may 
be  noted  that  the  new  information  for  this  edi- 
tion was  chosen  from  more  than  25,000  issues  of 
the  approximately  400  medical,  pharmaceutical, 
biological,  and  chemical  journals  which  are  regu- 
larly available  to  the  editors  as  the  basis  for  re- 
vision of  the  DISPENSATORY. 

The  very  thorough  investigations  now  required 
for  new  drugs  before  they  are  released  for  clinical 
use,  together  with  the  more  extensive  clinical 
reporting  of  them,  has  inevitably  resulted  in 
lengthier  monographs  concerning  individual  drugs. 
Since  oftimes  our  readers  may  wish  to  have  only 
the  most  essential  information  concerning  uses  of 
a  drug,  we  have  provided  for  the  lengthier  articles 
a  brief  outline  of  uses  at  the  beginning  of  the  sec- 
tion thus  designated.  Where  the  articles  are  of 
necessity  very  long,  a  summary  section  has  also 
been  provided,  this  following  the  section  on  uses. 
Also,  to  facilitate  quick  location  of  specific  in- 
formation about  drugs  having  a  variety  of  actions 
and  uses,  the  monographs  have  been  conspicuously 
and  informatively  captioned  to  indicate  specific 
actions  and  uses. 

Dosage  data  have  been  considerably  amplified 
in  this  edition.  The  range  of  dose,  the  maximum 
single  dose,  and  the  maximum  total  dose  in  24 
hours  are  provided  for  most  drugs;  variations  of 
dosage  in  different  diseases  are  indicated  where 
such  information  is  required;  comparison  of  dif- 
ferent routes  of  administration  is  also  included 
where  a  choice  is  available.  Toxicological  data 
have  also  been  expanded  and  methods  of  treat- 
ment of  poisoning  are  described  in  sufficient  detail 
to  be  of  practical  utility. 

The  section  on  Veterinary  Uses  and  Doses  of 
Drugs,  which  was  introduced  in  the  24th  Edition 
of  the  Dispensatory  and  has  found  wide  accept- 
ance, has  been  enlarged  by  63  pages  both  by  in- 
clusion of  new  drugs  and  new  data  for  older  ones. 

To  provide  space  for  the  abundance  of  new 
material  included,  this  edition  contains  over  200 
pages  more  than  its  predecessor;  102  pages  more 
were  made  available  by  the  deletion  of  general 
tests,  processes  and  reagents  formerly  comprising 
Part  Three  of  the  DISPENSATORY  which,  while 
important,  are  of  secondary  importance  to  the 


viii  PREFACE 

main  purpose  of  this  book  in  providing  practical  names  are  listed  opposite  the  title  page;  it  has 

and   up-to-the-minute   information   about   drugs.  become    increasingly    apparent    in    this    fruitful 

Further  savings  of  space  were  made  by  deletion  or  period  of  medicinals  development  that  the  collabo- 

curtailment  of  information  concerning  drugs  which  ration  of  specialists  is  essential  in  order  to  provide 

are  no  longer  or  only  very  rarely  used;  the  editors  the  thorough  and  authoritative  treatment  of  the 

were  not  unmindful,  however,  of  the  expectation  subject  required  in  the  DISPENSATORY.  Finally, 

of  users  of  the  DISPENSATORY  to  find  infor-  the  many  contributions  of  Walter  Kahoe,  Ph.D., 

mation    concerning    unusual    drugs.    A   new   and  Director  of   the   Medical  Department   of   J.   B. 

somewhat  more   condensed   typography   in   Part  Lippincott  Company,  toward  the  culmination  of 

Two  permitted  more  information  to  be  included  the  editorial  effort  in  the  production  of  the  printed 

therein.  book    are    not    only    acknowledged    but    greatly 

appreciated. 
The  editors  and  associate  editors  acknowledge  ARTHUR  OSOL, 

especially  the  assistance  of  the  contributors  whose  Editor-in-Chief 


Contents 

Page 

ABBREVIATIONS    xi 

PART  ONE:  Drugs  recognized  by  The  United  States  Pharmacopeia, 
British  Pharmacopoeia,  International  Pharmacopoeia,  or  The  Na- 
tional Formulary 1 

PART  TWO:  Drugs  not  official  in  The  United  States  Pharmacopeia, 
British  Pharmacopoeia,  International  Pharmacopoeia,  or  The  Na- 
tional Formulary 1523 

PART  THREE:  Veterinary  Uses  and  Doses  of  Drugs 1935 

INDEX  2059 


ABBREVIATIONS 


A.A.A.S. — The  American  Association  for  the  Advance- 
ment of  Science. 
A.M.A. — The  American  Medical  Association. 
Acta  chir.  Scandinav .—Acta  chirurgica  Scandinavica. 
Acta  dermato-venereol. — Acta  dermato-venerologica. 
Acta  med.  Scandinav. — Acta  medica  Scandinavica. 
Advances  Enzymol. — Advances   in   Enzymology   and 

Related  Subjects  of  Biochemistry. 
Allg.  med.  Centr.-Ztg. — Allegmeine  medicinische  Cen- 

tral-Zeitung. 
Am.  Drug. — American  Druggist. 
Am.  Fur  Breeder — American  Fur  Breeder. 
Am.  Heart  J. — American  Heart  Journal. 
Am.  J.  Anat. — American  Journal  of  Anatomy. 
Am.  J.  Bot. — American  Journal  of  Botany. 
Am.  J.  Cancer. — American  Journal  of  Cancer. 
Am.   J.   Clin.   Path. — American    Journal   of    Clinical 

Pathology. 
Am.  J.  Digest.  Dis. — American  Journal  of  Digestive 

Diseases  and  Nutrition. 
Am.  J.  Dis.  Child. — American  Journal  of  Diseases  of 

Children. 
Am.  J.  Hyg. — American  Journal  of  Hygiene. 
Am.  J.  Med. — American  Journal  of  Medicine. 
Am.  J.  Med.  Sc. — American  Journal  of  Medical  Sci- 
ences. 
Am.  J.  Obst.  Gyn.— American  Journal  of  Obstetrics 

and  Gynecology. 
Am.  J.  Ophth. — American  Journal  of  Ophthalmology. 
Am.  J.  Path. — American  Journal  of  Pathology. 
Am.  J.  Pharm. — American  Journal  of  Pharmacy. 
Am.  J.  Physiol. — American  Journal  of  Physiology. 
Am.  J.  Psychiat. — American  Journal  of  Psychiatry. 
Am.   J.   Pub.   Health — American   Journal   of   Public 

Health  and  the  Nation's  Health. 
Am.  J.  Roentgen. — American  Journal  of  Roentgen- 
ology and  Radium  Therapy. 
Am.  J.  Surg. — American  Journal  of  Surgery. 
Am.  J.  Syph.  Gonor.  Ven.  Dis. — American  Journal  of 

Syphilis,  Gonorrhea  and  Venereal  Diseases. 
Am.  J.  Syph.  Neurol. — American  Journal  of  Syphilis 

and  Neurology.  (Now  Am.  J.  Syph.  Gonor.  Ven. 

Dis.) 
Am.  J.  Trop.  Med. — American  Journal  of  Tropical 

Medicine. 
Am.  J.   Vet.  Res. — American  Journal  of  Veterinary 

Research. 
Am.  Med. — American  Medicine. 
Am.  Perfumer — American  Perfumer  and  Essential  Oil 

Review. 
Am.  Pract.  Dig.   Treat. — American   Practitioner   and 

Digest  of  Treatment. 
Am.  Prof.  Pharm. — American  Professional  Pharmacist. 
Am.  Rev.  Soviet  Med. — American  Review  of  Soviet 

Medicine. 
Am.  Rev.  Tuberc. — American  Review  of  Tuberculosis. 
Am.  Surg. — The  American  Surgeon. 
Am.  Vet.  Rev. — American  Veterinary  Review. 
Anais  faculdade  med.  univ.  S.  Paulo — Anais  da  facul- 

dade  de  medicina  da  universidade  de  Sao  Paulo. 
Analyst — The  Analyst. 
Anesth. — Anesthesiology. 
Aneth.  &  Analg. — Current  Researches  in  Anesthesia 

and  Analgesia. 
Angewandte  Chem. — Angewandte  Chemie. 
Ann.  Allergy — Annals  of  Allergy. 
Ann.  Biochem.  Exp.  Med. — Annals  of  Biochemistry 

and  Experimental  Medicine. 
Ann.  Chem. — Annalen  der  Chemie,  Liebig. 


Ann.  Chem.  Pharm. — Annalen  der  Chemie  und  Phar- 

macie.  (Now  Ann.  Chem.) 
Ann.  chim.  app. — Annali  di  chimica  applicata. 
Ann.  Chim.  Phys. — Annales  de  Chimie  et  de  Physique. 
Ann.  d'igiene — Annali  d'igiene. 
Ann.  dermat.  syph. — Annales  de  dermatologie  et  de 

syphiligraphie. 
Ann.  Inst.  Pasteur — Annales  de  l'lnstitut  Pasteur. 
Ann.  Int.  Med. — Annals  of  Internal  Medicine. 
Ann.  med.-psychol. — Annales  medico-psychologiques. 
Ann.  N.  Y.  Acad.  Sc. — Annals  of  the  New  York  Acad- 
emy of  Science. 
Ann.  Otol.  Rhin.  Larytig. — Annals  of  Otology,  Rhi- 

nology  and  Laryngology. 
Ann.  Rev.  Biochem. — Annual  Review  of  Biochemistry. 
Ann.  Rev.  Physiol.— Annual  Review  of  Physiology. 
Ann.  Surg. — Annals  of  Surgery. 
Ann.  Trop.  Med. — Annals  of  Tropical  Medicine  and 

Parasitology. 
Ann.  West.  Med.  Surg. — Annals  of  Western  Medicine 

and  Surgery. 
Antibiot.  Chemother. — Antibiotics  and  Chemotherapy. 
Apoth.-Ztg. — Apotheker-Zeitung.   (See  also  Deutsche 

Apoth.-Ztg.) 
Arbeit,  pharmakol.  Inst.  Dorpat — Arbeiten  der  phar- 

makologisches  Institut,  Dorpat. 
Arch.  Dermat.  Syph. — Archives  of  Dermatology  and 

Syphilology. 
Arch.  Dis.  Child. — Archives  of  Disease  in  Children. 
Arch.  exp.  Path.  Pharm. — Archiv  fur  experimentelle 

Pathologie  und  Pharmakologie. 
Arch,  farmacol.  sper. — Archivo  di  farmacologia  speri- 

mentale  e  scienze  affini. 
Arch,   farmacol.   terap. — Archivio   di   farmacologia   e 

terapeutica. 
Arch.  gen.  med. — Archives  generates  de  medecine. 
Arch.  ges.  Physiol. — Archiv  fiir  die   gesamte  Physi- 
ologic des  Menschen  und  der  Tiere. 
Arch.    Gewerbepath.    Gewerbehyg. — Archiv    fiir    Ge- 

werbepathologie  und  Gewerbehygiene. 
Arch.  Gyndk. — Archiv  fiir  Gynakologie. 
Arch.  Hyg.— Archiv  fiir  Hygiene  und  Bakteriologie. 
Arch.  Int.  Med.- — Archives  of  Internal  Medicine. 
Arch.  Indust.  Hyg. — Archives  of  Industrial  Hygiene 

and  Occupational  Medicine. 
Arch,  internat.   pharmacodyn.   therap. — Archives   in- 

ternationales  de  pharmacodynamic  et  de  therapie. 
Arch.  mal.  du  coeur — Archives  des  maladies  du  cceur  et 

des  vaisseaux. 
Arch.  Neurol.  Psychiat. — Archives  of  Neurology  and 

Psychiatry. 
Arch.  Ophth. — Archives  of  Ophthalmology. 
Arch.  Otolaryng. — Archives  of  Otolaryngology. 
Arch.  Path. — Archives  of  Pathology. 
Arch.  Path.  Lab.  Med. — Archives  of  Pathology  and 

Laboratory  Medicine.  (Now  Arch.  Path.) 
Arch.  Pediat. — Archives  of  Pediatrics. 
Arch,    pediat.    Uruguay — Archivos   de   pediatria   del 

Uruguay. 
Arch.  Pharm. — Archiv  der  Pharmacie. 
Arch.  Phys.  Med. — Archives  of  Physical  Medicine. 
Arch.  Phys.  Ther. — Archives  of  Physical  Therapy. 
Arch.  Schiffs-Tropen-Hyg. — Archiv   fiir  Schiffs-   und 

Tropen-Hygiene. 
Arch.  Surg. — Archives  of  Surgery. 
Arch.  urug.  de  med. — Archivos  uruguayos  de  medi- 
cina, cirugia  y  especialidades. 
Aust.  Vet.  J. — Australian  Veterinary  Journal. 


XII 


ABBREVIATIONS 


Australasian  J.  Pharm. — Australasian  Journal  of  Phar- 
macy. 

Australia,  Council  for  Sc.  &  Indust.,  Res.  Bull. — Aus- 
tralia, Council  for  Science  and  Industry,  Research 
Bull. 

Bact.  Rev. — Bacteriological  Reviews. 

Beitr.  Klin.  Tuberk. — Beitrage  zur  Klinik  der  Tuber- 
kulose  und  spezifischen  Tuberkulose-Forschung. 

Ber. — Berichte  der  deutschen  chemischen  Gesellschaft. 

Ber.  deutsch.  pharm.  Ges. — Berichte  der  deutschen 
pharmaceutischen  Gesellschaft. 

Ber.  ges.  Physiol. — Berichte  iiber  die  gesamte  Physi- 
ologic und  experimentelle  Pharmakologie. 

Berl.  klin.  Wchnschr. — Berliner  klinische  Wochen- 
schrift.  (Now  Klin.  Wchnschr.) 

Berl.  tierarztl.  Wchnschr. — Berliner  tierarztliche  Wo- 
chenschrift. 

Biochem.  J. — Biochemical  Journal. 

Biochem.  Ztschr. — Biochemische  Zeitschrift. 

Bol.  assoc.  brasil.  farm. — Boletim  da  associaqao  brasil- 
eira  de  farmaceuticos. 

Bol.  ministerio  agr. — Boletim  do  ministerio  da  agri- 
cultura  (Brazil). 

Boll.  chim.  farm. — Bollettino  chimico-farmaceutico. 

Boston  Med.  Surg.  J. — Boston  Medical  and  Surgical 
Journal.  (Now  New  Eng.  J.  Med.) 

Bot.  Abs. — Botanical  Abstracts. 

Bot.  Centralbl. — Botanisches  Centralblatt. 

Bot.  Gaz. — Botanical  Gazette. 

B.P. — The  British  Pharmacopoeia. 

B.P.  Add. — Addendum  to  the  British  Pharmacopoeia. 

Brasil-med. — Brasil-medico. 

Brit.  Heart  J. — British  Heart  Journal. 

Brit.  J.  Derm. — British  Journal  of  Dermatology. 

Brit.  J.  Anaesth. — British  Journal  of  Anaesthesia. 

Brit.  J.  Exp.  Path. — British  Journal  of  Experimental 
Pathology. 

Brit.  J.  Ind.  Med. — British  Journal  of  Industrial 
Medicine. 

Brit.  J.  Ophth. — British  Journal  of  Ophthalmology. 

Brit.  J.  Pharmacol.  Chemother. — British  Journal  of 
Pharmacology  and  Chemotherapy. 

Brit .  J.  Phys.  Med. — British  Journal  of  Physical  Medi- 
cine and  Industrial  Hygiene. 

Brit.  J.  Radiol. — British  Journal  of  Radiology. 

Brit.  J.  Surg. — British  Journal  of  Surgery. 

Brit.  J.  Tuberc. — British  Journal  of  Tuberculosis. 

Brit.  J.  Urol. — British  Journal  of  Urology. 

Brit.  M.  J. — British  Medical  Journal. 

Brit.  Vet.  J. — British  Veterinary  Journal. 

Brodil'naya  Prom. — Brodil'naya  Promyshlennost. 

Bruxelles-med. — Bruxelles-medical. 

Bull.  A.  S.  H.  P. — Bulletin  of  the  American  Society  of 
Hospital  Pharmacists. 

Bull.  Acad.  med.  Paris — Bulletin  de  l'Academie  de 
medecine. 

Bull.  Acad.  Med.  Toronto — Bulletin  of  the  Academy 
of  Medicine,  Toronto. 

Bull.  Am.  Coll.  Surgeons — Bulletin  of  the  American 
College  of  Surgeons. 

Bull,  assoc.  chim. — Bulletin  de  l'association  des 
chimistes. 

Bull.  Chem.  Soc.  Japan — Bulletin  of  the  Chemical 
Society  of  Japan. 

Bull.  gen.  therap. — Bulletin  general  de  therapeutique 
medicale,  chirurgicale,  obstetricale  et  pharma- 
ceutique. 

Bull.  Health  Leag.  Nations — Bulletin  of  the  Health 
Organization,  League  of  Nations. 

Bull.  Hist.  Med—  Bulletin  of  the  Institute  of  the  His- 
tory of  Medicine. 

Bull.  Hyg. — Bulletin  of  Hygiene. 

Bull.  Johns  Hopkins  Hosp. — Bulletin  of  the  Johns 
Hopkins  Hospital. 

Bull.  med. — Le  bulletin  medical. 


Bull.  Nat.  Inst.  Health— Bulletin  of  the  National  In- 
stitutes of  Health. 

Bull.  New  Eng.  Med.  Center — Bulletin  of  the  New 
England  Medical  Center. 

Bull.  N.  F.  Com. — Bulletin  of  the  National  Formulary 
Committee. 

Bull.  N.  Y.  Acad.  Med.— Bulletin  of  the  New  York 
Academy  of  Medicine. 

Bull.  Pharm. — Bulletin  of  Pharmacy. 

Bull.  Rheumat.  Dis. — Bulletin  on  Rheumatic  Diseases. 

Bull.  sc.  Pharmacol. — Bulletin  des  sciences  pharma- 
cologiques. 

Bull.  Sch.  Med.  Univ.  Maryland — Bulletin  of  the 
School  of  Medicine,  University  of  Maryland. 

Bull.  soc.  chim. — Bulletin  de  la  societe  chimique  de 
France. 

Bull.  soc.  chim.  Belg. — Bulletin  de  la  societes  chim- 
iques  Beiges. 

Bidl.  soc.  chim.  biol. — Bulletin  de  la  societe  de  chimie 
biologique. 

Bull.  soc.  franc,  dermat.  syph. — Bulletin  de  la  societe 
franchise  de  dermatologie  et  de  syphiligraphie. 

Bull.  soc.  med. — Bulletins  et  memoires  de  la  societe 
medicale  des  hopitaux  de  Paris. 

Bull.  soc.  path.  exot. — Bulletin  de  la  societe  de  path- 
ologie  exotique  et  de  ses  filiales. 

Bull.  St.  Louis  M.  Soc. — Bulletin  of  the  St.  Louis 
Medical  Society. 

Bidl.  Torrey  Bot.  Club— Bulletin  of  the  Torrey  Bo- 
tanical Club. 

Bull.  trav.  soc.  pharm.  Bordeaux — Bulletin  des  travaux 
de  la  societe  de  pharmacie  de  Bordeaux. 

Bull.  U.  S.  Army  M.  Dept—  Bulletin  of  the  United 
States  Army  Medical  Department. 

Bull.  War  Med. — Bulletin  of  War  Medicine. 

Bur.  Standards  J.  Research — Bureau  of  Standards 
Journal  of  Research. 

Calif.  &  West.  Med. — California  and  Western  Medi- 
cine. 

Calif.  Med. — California  Medicine. 

Can.  J.  Comp.  Med.— Canadian  Journal  of  Compara- 
tive Medicine  and  Veterinary  Science. 

Can.  J.  Research — Canadian  Journal  of  Research. 

Can.  Med.  Assoc.  J. — Canadian  Medical  Association 
Journal. 

Can.  Pharm.  J. — Canadian  Pharmaceutical  Journal. 

Can.  Pub.  Health  J. — Canadian  Public  Health  Journal. 

Can.  Vet.  Rec. — Canadian  Veterinary  Record. 

Cancer  Res. — Cancer  Research. 

Centralbl.  med.  Wissensch. — Centralblatt  fur  die  medi- 
zinischen  Wissenschaften. 

Cereal  Chem. — Cereal  Chemistry. 

Chem.  Abs. — Chemical  Abstracts. 

Chem.  Centralbl. — Chemisches  Centralblatt. 

Chem.  Drug. — The  Chemist  and  Druggist. 

Chem.  Eng.  News — Chemical  and  Engineering  News. 

Chem.  Industries — Chemical  Industries. 

Chem.  Met.  Eng. — Chemical  and  Metallurgical  Engi- 
neering. 

Chem.  News — Chemical  News  and  Journal  of  In- 
dustrial Science. 

Chem.  Rev. — Chemical  Reviews. 

Chem.  Trade  J. — Chemical  Trade  Journal  and  Chem- 
ical Engineer. 

Ckem.-Ztg. — Chemiker-Zeitung. 

Chimica  e  I'industria  Milan — La  chimica  e  l'industria, 
Milan. 

Chinese  J.  Physiol. — Chinese  Journal  of  Physiology. 

Chinese  M.  J. — Chinese  Medical  Journal. 

Cincinnati  J.  Med.— Cincinnati  Journal  of  Medicine. 

Cincinnati  M.  J. — Cincinnati  Medical  Journal. 

Cleveland  Clin.  Quart. — Cleveland  Clinic  Quarterly. 

Cleveland  M.  J. — Cleveland  Medical  Journal. 

Clin.  J. — Clinical  Journal. 

Clin.  Med. — Clinical  Medicine. 

Clin.  Proc. — Clinical  Proceedings. 


ABBREVIATIONS 


XIII 


Clin.  Sc. — Clinical  Science. 

Clinics — Clinics. 

Colorado   Med. — Colorado    Medicine.    (Now    Rocky 

Mountain  M.  J.) 
Compt.  rend.  acad.  sc. — Comptes   rendus   hebdoma- 

daires  des  seances  de  l'academie  des  sciences. 
Compt.  rend.  soc.  biol. — Comptes  rendus  des  seances 

de  la  societe  de  biologic 
Confinia  Neurol. — Confinia  Neurologica. 
Connecticut  State  M.  /.—Connecticut  State  Medical 

Journal. 
Cornell  Vet. — The  Cornell  Veterinarian. 
Dansk  Tids.  Farm. — Dansk  Tidsskrift  for  Farmaci. 
Delaware  S.  M.  J. — Delaware  State  Medical  Journal. 
Dental  Rec. — Dental  Record. 
Dental  Survey — Dental  Survey. 
Dentistry — Dentistry,  a  Digest  of  Practice. 
Derm.  Wchnschr. — Dermatologische  Wochenschrift. 
Derm.  Ztschr. — Dermatologische  Zeitschrift. 
Deutsche  Apoth.-Ztg. — Deutsche  Apotheker-Zeitung. 
Deutsche  med.  7.— Deutsches  medizinisches  Journal. 
Deutsche    med.    Wchnschr. — Deutsche    medicinische 

Wochenschrift. 
Deutsche  Mil. — Deutsche  Militararzt. 
Deutsche    tierarztl.    Wochenschr. — Deutsche    tierarzt- 

liche  Wochenschrift. 
Deutsche   zahnarztl.   Wchnschr. — Deutsche   zahnarzt- 

liche  Wochenschrift. 
Deutsche  Ztschr.  ges.  gerichtl.  Med. — Deutsche  Zeit- 
schrift fur  die  gesamte  gerichtliche  Medizin. 
Deutsches  Arch.   klin.   Med. — Deutsches   Archiv    fur 

klinische  Medizin. 
Dis.  Nerv.  Syst. — Diseases  of  the  Nervous  System. 
Drug.  Circ. — Druggists  Circular. 
Drug  Cosmet.  Ind. — Drug  and  Cosmetic  Industry. 
East  African  M.  J. — East  African  Medical  Journal. 
Edinburgh  M.  J. — Edinburgh  Medical  Journal. 
Endocrinology — Endocrinology. 
Enzymologia — Enzymologia. 
Ergebn.    Enzymforsch. — Ergebnisse    der    Enzymfor- 

schung. 
Exp.    Med.    &    Surg. — Experimental    Medicine    and 

Surgery. 
Eye,  Ear,  Nose  &  Throat  Monthly — Eye,  Ear,  Nose 

and  Throat  Monthly. 
Farm.  Revy — Farmacevtisk  Revy. 
Farmakol.  i  Toksikol. — Farmakologiia  i  Toksikologiia. 
Fed.  Proc. — Federation  Proceedings. 
Fettchem.  Umschau — Fettchemische  Umschau.   (Now 

Fette  und  Seifen.) 
Fette  und  Seifen — Fette  und  Seifen. 
Folia  Medica — Folia  Medica,  Naples. 
Food  Res. — Food  Research. 
Fortschr.  Med. — Fortschritte  der  Medizin. 
Fortschr.  Ther. — Fortschritte  der  Therapie. 
Fr. — French  Codex. 
Gastroenterology — Gastroenterology. 
Gaz.  chim.  ital.- — Gazzetta  chimica  italiana. 
Gaz.  med.  de   France — Gazette   medicale  de   France 

et  des  pays  de  langue  franchise. 
Gaz.  med.  Paris — Gazettes  medicale,  Paris. 
Ger. — German  Pharmacopoeia. 
Geriatrics — Geriatrics. 
Guy's  Hosp.  Rep. — Guy's  Hospital  Reports. 
Heart — Heart. 
Heilkunde — Heilkunde. 
Helv.  Chim.  Acta — Helvetica  Chimica  Acta. 
Helv.  Physiol.  Pharm.  Acta — Helvetica  Physiologica  et 

Pharmacologica  Acta. 
Herbarist — Herbarist. 
Human  Fert. — Human  Fertility. 
Hyg.  Lab.  Bull. — Hygienic  Laboratory  Bulletin.  (Now 

Bull.  Nat.  Inst.  Health.) 
Illinois  M.  J. — Illinois  Medical  Journal. 
Ind.    Chemist — Industrial     Chemist    and     Chemical 

Manufacturer. 


Ind.  Eng.  Chem. — Industrial  and  Engineering  Chem- 
istry. 

Ind.  Eng.  Chem.,  Anal.  Ed. — Industrial  and  Engi- 
neering Chemistry,  Analytical  Edition. 

Ind.  Med. — Industrial  Medicine. 

Indian  J.  Med.  Res. — Indian  Journal  of  Medical  Re- 
search. 

Indian  J.  Pharm. — Indian  Journal  of  Pharmacy. 

Indian  Med.  Gaz. — Indian  Medical  Gazette. 

Indian  Vet.  J. — The  Indian  Veterinary  Journal. 

Indiana  State  M.  A.  J. — Indiana  State  Medical  Asso- 
ciation Journal. 

Internat.  Clin. — International  Clinics.  (Now  New 
Internat.  Clin.) 

Internat.  J.  Med.  Surg. — International  Journal  of 
Medicine  and  Surgery. 

Internat.  Med.  Digest — International  Medical  Digest. 

Internat.  Rec.  Med. — International  Record  of  Medi- 
cine and  General  Practice  Clinics. 

It. — Italian  Pharmacopoeia. 

J.A.CS. — Journal  of  the  American  Chemical  Society. 

/.  A.  Dent.  A. — Journal  of  the  American  Dental 
Association. 

/.  A.  Dietet.  A. — Journal  of  the  American  Dietetic 
Association. 

/.  A.  Inst.  Homeopathy — Journal  of  the  American 
Institute  of  Homeopathy. 

J. A.M. A. — Journal  of  the  American  Medical  Asso- 
ciation. 

J.  A.  M.  Women's  A. — Journal  of  the  American  Medi- 
cal Women's  Association. 

J.A.O.A.C. — Journal  of  the  Association  of  Official 
Agricultural  Chemists. 

/.  A.  Ph.  A. — Journal  of  the  American  Pharmaceu- 
tical Association. 

J.  A.  Ph.  A.,  Prac.  Ed. — Journal  of  the  American 
Pharmaceutical  Association,  Practical  Edition. 

J.A.V.M.A. — Journal  of  the  American  Veterinary 
Medical  Association. 

/.  Agric.  Food  Chem. — Journal  of  Agricultural  and 
Food  Chemistry. 

/.  Agric.  Res. — Journal  of  Agricultural  Research. 

/.  Agric.  Sc. — The  Journal  of  Agricultural  Science. 

/.  Albert  Einstein  Med.  Center — Journal  of  the  Albert 
Einstein  Medical  Center. 

/.  Allergy— The  Journal  of  Allergy. 

/.  Anat. — Journal  of  Anatomy. 

/.  Ani.  Sc. — Journal  of  Animal  Science. 

/.  Bad. — Journal  of  Bacteriology. 

J.  Biol.  Chem. — Journal  of  Biological  Chemistry. 

/.  Bone  Joint  Surg. — Journal  of  Bone  and  Joint 
Surgery. 

/.  Calif.  State  Dent.  A. — Journal  of  the  California 
State  Dental  Association. 

J.  Can.  Dent.  A. — Journal  of  the  Canadian  Dental 
Association. 

/.  Chem.  Educ. — Journal  of  Chemical  Education. 

/.  Chem.  Ind. — Journal  of  Chemical  Industry  (Mos- 
cow). 

/.  Chem.  S. — Journal  of  the  Chemical  Society. 

/.  Chemother. — Journal  of  Chemotherapy. 

/.  chim.  phys. — Journal  de  chimie  physique. 

/.  Clin.  Endocrinol. — Journal  of  Clinical  Endocrinol- 
ogy. 

/.  Clin.  Inv. — Journal  of  Clinical  Investigation. 

J.  Clin.  Nutrition — Journal  of  Clinical  Nutrition. 

J.  Comp.  Path.  Therap. — The  Journal  of  Comparative 
Pathology  and  Therapeutics. 

/.  Council  Sci.  Ind.  Res. — Journal  of  the  Council  for 
Scientific  and  Industrial  Research. 

/.  Cutan.  Dis. — Journal  of  Cutaneous  Diseases  includ- 
ing Syphilis. 

J.  Dairy  Sc. — Journal  of  Dairy  Science. 

/.  Dent.  Research — Journal  of  Dental  Research. 

/.  Econ.  Entomol. — Journal  of  Economic  Entomology. 

/.  Endocrinol. — Journal  of  Endocrinology. 


XIV 


ABBREVIATIONS 


/.  Exp.  Med. — Journal  of  Experimental  Medicine. 

/.  Gen.  Client.  (US.S.R.)—  Journal  of  General  Chem- 
istry (U.S.S.R.). 

J.  Gen.  Microbiol. — Journal  of  General  Microbiology. 

/.  Gen.  Physiol. — Journal  of  General  Physiology. 

J.  Geront. — Journal  of  Gerontology. 

J.  Hygiene — Journal  of  Hygiene. 

/.  Immunol. — Journal  of  Immunology. 

/.  Ind.  Hyg.  Toxicol. — Journal  of  Industrial  Hygiene 
and  Toxicology. 

/.  Indian  Chem.  S. — Journal  of  the  Indian  Chemical 
Society. 

/.  Indian  Inst.  Sc. — Journal  of  the  Indian  Institute  of 
Science. 

/.   Indian   M.   A. — Journal   of    the    Indian    Medical 
Association. 

/.    Indiana   M.    A. — Journal   of    the    Indiana    State 
Medical  Association. 

/.  Inject.  Dis. — Journal  of  Infectious  Diseases. 

/.  Internat.  Col.  Surg. — Journal  of  the  International 
College  of  Surgeons. 

J.  Invest.  Dermat. — Journal  of  Investigative  Derma- 
tology. 

/.   Iowa  M.  Soc. — Journal   of   Iowa   State   Medical 
Society. 

/.  Lab.  Clin.  Med. — Journal  of  Laboratory  and  Clini- 
cal Medicine. 

J. -Lancet — Journal-Lancet. 

/.  Laryng.  Otol. — Journal  of  Laryngology  and  Otol- 
ogy. 

J.  Linn.  Soc. — Journal  of  the  Linnaean  Society. 

J.  M.  A.  Alabama — Journal  of  the  Medical  Associa- 
tion of  the  State  of  Alabama. 

J.  M.  A.  Georgia — Journal  of  the  Medical  Association 
of  Georgia. 

/.  M.  Soc.  New  Jersey — Journal  of  the  Medical  So- 
ciety of  New  Jersey. 

/.  Maine  M.  A. — Journal  of  the  Maine  Medical  Asso- 
ciation. 

J.  mid.  chirurg.  prat. — Journal  de   medecine  et  de 
chirurgie  pratiques. 

/.  mid.  Lyon — Le  journal  de  medecine  de  Lyon. 

/.  mid.  Paris — Journal  de  medecine  de  Paris. 

J.  Ment.  Sc. — Journal  of  Mental  Science. 

J.   Michigan   M.    Soc. — Journal    of    Michigan    State 
Medical  Society. 

/.  Missouri  M.  A. — Journal  of  Missouri  State  Medical 
Association. 

/.  Mt.  Sinai  Hosp. — Journal  of  the  Mount  Sinai  Hos- 
pital, New  York. 

/.  Nat.  Cancer  Inst. — Journal  of  the  National  Cancer 
Institute. 

J.   Nat.   M.   A. — Journal   of    the    National   Medical 
Association. 

/.  Nat.  Malaria  Soc. — Journal  of  the  National  Malaria 
Society. 

/.  Nerv.  Ment.  Dis. — Journal  of  Nervous  and  Mental 
Disease. 

/.  Neurophysiol. — Journal  of  Neurophysiology. 

/.  Neurosurg. — Journal  of  Neurosurgery. 

/.  Nutrition — The  Journal  of  Nutrition. 

/.  Obst.  Gyn.  Br.  Emp. — Journal  of  Obstetrics  and 
Gynaecology  of  the  British  Empire. 

/.  Oil  &  Colour  Chem.  Assoc. — Journal  of  the  Oil 
and  Colour  Chemists'  Association. 

/.  Omaha  Mid-West  Clin.  Soc. — Journal  of  the  Omaha 
Mid-West  Clinical  Society. 

/.  Oral  Surg. — Journal  of  Oral  Surgery. 

/.  Org.  Chem. — Journal  of  Organic  Chemistry. 

/.  Parasitol. — Journal  of  Parasitology. 

/.  Parenteral  Therapy — Journal  of  Parenteral  Ther- 
apy. 

/.  Path.  Bad. — Journal  of  Pathology  and  Bacteriol- 
ogy. 

/.  Pediatr. — Journal  of  Pediatrics. 


J.  pharm.  Alsace  Lorraine — Journal  de  pharmacie 
d'Alsace  et  de  Lorraine. 

J.  pharm.  Belg. — Journal  de  pharmacie  de  Belgique. 

/.  pharm.  chim. — Journal  de  pharmacie  et  de  chimie. 

/.  Pharm.  Pharmacol. — The  Journal  of  Pharmacy  and 
Pharmacology. 

J.  Pharm.  Soc.  Japan — Journal  of  the  Pharmaceutical 
Society  of  Japan. 

/.  Pharmacol. — Journal  of  Pharmacology  and  Experi- 
mental Therapeutics. 

/.  Phys.  Chem. — Journal  of  Physical  Chemistry. 

/.  Physiol. — Journal  of  Physiology. 

/.  prakt.  Chem. — Journal  fvir  praktische  Chemie. 

/.  Prevent.  Med. — Journal  of  Preventive  Medicine. 

J.  Proc.  Roy.  Soc.  N.  S.  Wales — Journal  and  Proceed- 
ings of  the  Royal  Society  of  New  South  Wales. 

/.  Roy.  Army  Med.  Corps — Journal  of  the  Royal 
Army  Medical  Corps. 

/.  Roy.  Soc.  W.  Australia — Journal  of  the  Royal  So- 
ciety of  Western  Australia. 

/.  Russ.  Phys.  Chem.  S. — Journal  of  the  Russian 
Physical-Chemical  Society. 

/.  Soc.  Chem.  Ind. — Journal  of  the  Society  of  Chemi- 
cal Industry. 

/.  South  African  V.  M.  A. — The  Journal  of  the  South 
African  Veterinary  Medical  Association. 

/.  Thoracic  Surg.- — Journal  of  Thoracic  Surgery. 

/.  Trop.  Med.  Hyg. — Journal  of  Tropical  Medicine 
and  Hygiene. 

/.  Urol. — The  Journal  of  Urology. 

J.  Ven.  Dis.  Inform. — Journal  of  Venereal  Disease 
Information. 

Jahresber.  Pharm. — Jahresbericht  der  Pharmazie. 

Jap.  J.  Med.  Sc. — Japanese  Journal  of  Medical  Sci- 
ences. 

Kentucky  M.  J. — Kentucky  Medical  Journal. 

Klin.  Monatsbl.  Augen. — Klinische  Monatsblatter  fur 
Augenheilkunde. 

Klin.-therap.  Wchnschr.  —  Klinisch-therapeutische 
Wochenschrift. 

Klin.  Wchnschr. — Klinische  Wochenschrift. 

Kunststoffe — Kunststoffe:  Zeitschrift  fur  Erzeugung 
und  Venvendung  veredelter  oder  chemisch  herges- 
tellter  Stoffe. 

Lahey  Clin.  Bull.- — Lahey  Clinic  Bulletin. 

Lancet — The  Lancet. 

Laryng. — Laryngoscope. 

Laval  mid. — Laval  medical. 

L'Union  pharm. — L'Union  pharmaceutique. 

M.  S.  C.  Vet. — The  M.  S.  C.  Veterinarian. 

Med.  Ann.  District  Columbia — Medical  Annals  of  the 
District  of  Columbia. 

Med.  Bl. — Medicinische  Blaetter. 

Med.  Bull.  Vet.  Admin.— Medical  Bulletin  of  the 
Veterans'  Administration. 

Med.  Clin.  North  America — The  Medical  Clinics  of 
North  America. 

Med.  J.  Australia — Medical  Journal  of  Australia. 

Med.  Klin. — Medizinische  Khnik. 

Med.  Press— Medical  Press  and  Circular. 

Med.  Rec. — Medical  Record. 

Med.  Rund. — Medizinische  Rundschau. 

Med.  Times— Medical  Times. 

Medecine — La  Medecine. 

Medicine — Medicine:  Analytical  Reviews  of  General 
Medicine,  Neurology  and  Pediatrics. 

Merck  Rep— The  Merck  Report. 

Merck's  Jahresber. — Merck's  Jahresbericht  uber  Neu- 
erungen  auf  den  Gebieten  der  Pharmakotherapie 
und  Pharmazie. 

Mfg.  Chemist— The  Manufacturing  Chemist. 

Mfg.  Perfumer — The  Manufacturing  Perfumer. 
(Merged  with  Mfg.  Chemist.) 

Mikrochemie — Mikrochemie. 

MU.  Surg. — Military  Surgeon. 

Minn.  Med. — Minnesota  Medicine. 


ABBREVIATIONS 


xv 


Missouri  Agric.  Exp.  Sta.  Res.  Bull. — Missouri  Agri- 
cultural Experiment  Station  Research  Bulletin. 
Missouri  Med. — Missouri  Medicine. 
Mitt.  med.  Akad.  Kioto — Mitteilungen  aus  der  medi- 

zinischen  Akademie  zu  Kioto. 
Monatsh.  Chetn. — Monatshefte  fur  Chemie  und  ver- 

wandte  Teile  anderer  Wissenschaften. 
Monatsh.  f.   Vet.-tned. — Monatshefte   fur   Veterinar- 

medizin. 
Monatsh.   prakt.    Tierheilk. — Monatshefte   fiir   prak- 

tische  Tierheilkunde. 
Monatsschr.    Geburtsh.    Gyn'dk. — Monatsschrift    fiir 

Geburtshiilfe  und  Gynakologie. 
Munch,    med.    Wchnschr. — Munchener    medizinische 

Wochenschrift. 
N.  Carolina  M.  J. — North  Carolina  Medical  Journal. 
N.F. — The  National  Formulary,  Tenth  Edition. 
N.   Y.  State  J.  Med. — New  York  State  Journal  of 

Medicine. 
Nat.  Res.  Council  Bull. — National  Research  Council 

Bulletin. 
Nature — Nature. 
Nederland.     Tijdschr.    Pharm. — Nederlandsch    Tijd- 

schrift  voor  Pharmacie,  Chemie  en  Toxicologic 
New  Eng.  J.  Med. — New  England  Journal  of  Medi- 
cine. 
New  Internat.  Clin. — New  International  Clinics. 
New  Orleans  Med.  Surg.  J. — New   Orleans  Medical 

and  Surgical  Journal. 
North  Am.  Vet.- — The  North  American  Veterinarian. 
Northwest  Med. — Northwest  Medicine. 
Nouv.  Rem. — Nouveaux  Remedes. 
Nutrition  Rev. — Nutrition  Reviews. 
Obst.  Gyn. — Obstetrics  and  Gynecology. 
Occup.  Med. — Occupational  Medicine. 
Oesterr.      Chem.-Ztg.  —  Oesterreichische      Chemiker- 

Zeitung.  (Now  Wien.  Chem.-Ztg.) 
Ohio  State  M.  J. — Ohio  State  Medical  Journal. 
Oil  and  Fat  Ind. — Oil  and  Fat  Industries.  (Now  Oil 

and  Soap.) 
Oil  and  Soap — Oil  and  Soap. 
Oral  Surg.,  Oral  Med.,  Oral  Path— Oral  Surgery,  Oral 

Medicine  and  Oral  Pathology. 
Orient.  J.  Dis.  Infants — Oriental  Journal  of  Diseases 

of  Infants. 
Pediatr. — Pediatrics. 

Pennsylvania  M.  J. — Pennsylvania  Medical  Journal. 
Perf.    Ess.    Oil   Rec. — Perfumery    and    Essential    Oil 

Record. 
Pest,  med.-chirurg.  Presse — Pester  medicinisch-chirur- 

gische  Presse. 
Pharm.  Acta  Helv. — Pharmaceutica  Acta  Helvetiae. 
Pharm.  Arch. — Pharmaceutical  Archives. 
Pharm.  Era — Pharmaceutical  Era. 
Pharm.  J. — Pharmaceutical  Journal. 
Pharm.  Monatsh. — Pharmazeutische  Monatshefte. 
Pharm.  Presse — Pharmazeutische  Presse. 
Pharm.  Rev. — Pharmaceutical  Review. 
Pharm.  Rund. — Pharmaceutische  Rundschau. 
Pharm.    Tijdschr. — Pharmaceutisch    Tijdschrift    voor 

Nederlandsch-Indie. 
Pharm.  Weekblad — Pharmaceutisch  Weekblad. 
Pharm.     Zentr. — Pharmaceutische     Zentralhalle     fiir 

Deutschland. 
Pharm.  Ztg. — Pharmaceutische  Zeitung. 
Pharmacol.  Rev. — Pharmacological  Reviews. 
Phila.  Med. — Philadelphia  Medicine. 
Philippine  J.  Sc. — Philippine  Journal  of  Science. 
Physiol.  Rev. — Physiological  Reviews. 
Pittsburgh  Med.  Bull— Pittsburgh  Medical  Bulletin. 
Plast.  Reconstruct.  Surg. — Plastic  and  Reconstructive 

Surgery. 
Postgrad.  Med. — Postgraduate  Medicine. 
Poultry  Sc. — Poultry  Science. 
Pract . — Practitioner. 
Pract.  Drug. — Practical  Druggist. 


Praktika  Akad.  Athenon  —  Praktika  Akademia 
Athen5n. 

Prensa  med.  Argent. — La  prensa  medica  Argentina. 

Prensa  med.  Mexicana — Prensa  medica  Mexicana. 

Presse  med. — Presse  medicale. 

Proc.  A.  Diabetes  A. — Proceedings  of  the  American 
Diabetes  Association. 

Proc.  A.  Ph.  A. — Proceedings  of  the  American  Phar- 
maceutical Association. 

Proc.  Centr.  Soc.  Clin.  Res. — Proceedings  of  the 
Central  Society  for  Clinical  Research. 

Proc.  Chem.  S. — Proceedings  of  the  Chemical  Society. 

Proc.  Helminthol.  Soc. — Proceedings  of  the  Helmin- 
thological  Society. 

Proc.  Imp.  Acad.  Tokyo- — Proceedings  of  the  Im- 
perial Academy  (Tokyo). 

Proc.  Indian  Acad.  Sc. — Proceedings  of  the  Indian 
Academy  of  Sciences. 

Proc.  Indiana  Vet.  Med.  Assoc. — Proceedings  of  the 
Indiana  Veterinary  Medical  Association. 

Proc.  Int.  Congr.  PI.  Sc. — Proceedings  of  the  Inter- 
national Congress  of  Plant  Science. 

Proc.  Mayo — Proceedings  of  the  Staff  Meetings  of 
the  Mayo  Clinic. 

Proc.  Nat.  Acad.  Sc. — Proceedings  of  the  National 
Academy  of  Science. 

Proc.  N.  J.  Ph.  A. — Proceedings  of  the  New  Jersey 
Pharmaceutical  Association. 

Proc.  Penn.  Ph.  A. — Proceedings  of  the  Pennsylvania 
Pharmaceutical  Association. 

Proc.  Roy.  Soc.  London — Proceedings  of  the  Royal 
Society,  London. 

Proc.  Roy.  Soc.  Med. — Proceedings  of  the  Royal  So- 
ciety of  Medicine. 

Proc.  S.  Dakota  Acad.  Sc. — Proceedings  of  the  South 
Dakota  Academy  of  Sciences. 

Proc.  S.  Exp.  Biol.  Med. — Proceedings  of  the  Society 
for  Experimental  Biology  and  Medicine. 

Progres  med.- — Le  progres  medical. 

Psych.  Quart. — Psychiatric  Quarterly. 

Psychosom.  Med. — Psychosomatic  Medicine. 

Pub.  Health  Rep.— Public  Health  Reports. 

Puerto  Rico  J.  Pub.  Health — Puerto  Rico  Journal  of 
Public  Health  and  Tropical  Medicine. 

Quart.  Bull.  Northwest.  U.  Med.  Sch. — Quarterly  Bul- 
letin of  Northwestern  University  Medical  School. 

Quart.  J.  Exp.  Physiol. — Quarterly  Journal  of  Ex- 
perimental Physiology. 

Quart.  J.  Med.— Quarterly  Journal  of  Medicine. 

Quart.  J.  P. — Quarterly  Journal  of  Pharmacy  and 
Pharmacology. 

Quart.  J.  Stud.  Alcohol — Quarterly  Journal  of  Studies 
on  Alcohol. 

Queensland  Agr.  J. — Queensland  Agricultural  Journal. 

Radiology — Radiology. 

Rec.  trav.  chim. — Recueil  des  travaux  chimiques  des 
Pays-Bas. 

Rev.  assoc.  brasil.  farm. — Revista  da  associaqao  brasi- 
leira  de  farmaceuticos. 

Rev.  brasil.  med.  farm.— Revista  brasileira  de  medi- 
cina  e  farmacia. 

Rev .  Canad.  Biol. — Revue  Canadienne  de  Biologic 

Rev.  chim.  ind. — Revista  de  chimica  industrial  (Rio 
de  Janeiro). 

Rev.  din.  espan. — Revista  clinica  espanola. 

Rev.  filipina  med.  farm. — Revista  filipina  de  medicina 
y  farmacia. 

Rev.  flora  med. — Revista  de  flora  medicinal  (Rio  de 
Janeiro). 

Rev.  Gastroenterol. — The  Review  of  Gastroenterology. 

Rev.  gen.  Clin.  Therap. — Revue  generale  de  Clinique 
et  de  Therapeutique. 

Rev.  med.  hyg.  trop. — Revue  de  medecine  et  d'hy- 
giene  tropicales. 

Rev.  med.  Liege — Revue  medicale  de  Liege. 


XVI 


ABBREVIATIONS 


Rev.  med.  Suisse  Rom. — Revue  medicale  de  la  Suisse 
Romande. 

Rev.  neurol. — Revue  neurologique. 

Rev.  quim.  pura  aplic. — Revista  de  quimica  pura  e 
aplicada. 

Rev.  therap.  med.-chirurg. — Revue  de  therapeutique 
medico-chirurgicale. 

Riechstoff  Ind. — Riechstoff  Industrie. 

Rif.  med. — La  Riforma  medica. 

Rocky  Mountain  M.  J. — Rocky  Mountain  Medical 
Journal. 

Royal  Col.  Phys.  Rep.  Edinburgh — Royal  College  of 
Physicians  Laboratory  Reports,  Edinburgh. 

5.  Dakota  J.  M.  Pharm.— South  Dakota  Journal  of 
Medicine  and  Pharmacy. 

Sang — Le  sang. 

Sao  Paulo  med. — Sao  Paulo  medico. 

Schim.  Rep. — Schimmel  &  Co.,  Annual  Report. 

Schweiz.  Apoth.-Ztg.  —  Schweizerische  Apotheker- 
Zeitung. 

Schweiz.  Arch.  Tierheilk. — Schweizerische  Archiv  fiir 
Tierheilkunde. 

Schweiz.  med.  Wchnschr. — Schweizerische  medizinische 
Wochenschrift. 

Schweiz.  naturforsch.  Gesell. — Schweizerische  natur- 
forschende  Gesellschaft. 

Schweiz.  Wchnschr.  Pharm. — Schweizerische  Woch- 
enschrift fiir  Pharmacie. 

Sci.  Monthly — Scientific  Monthly. 

Science — Science. 

Scientia  Pharm. — Scientia  Pharmaceutica. 

Seifensieder-Ztg. — Seifensieder-Zeitung. 

Semaine  med. — Semaine  medicale. 

Semana  medica — La  Semana  medica. 

Skandinav.  Arch.  Physiol. — Skandinavisches  Archiv 
fiir  Physiologie. 

Soap,  Perf.  &  Cos. — Soap,  Perfumery  and  Cosmetics 
Trade  Journal. 

South  African  J.  Med.  Sc. — South  African  Journal 
of  Medical  Sciences. 

South.  M.  J. — Southern  Medical  Journal. 

South.  Med.  Surg. — Southern  Medicine  and  Surgery. 

Sp. — Spanish  Pharmacopoeia. 

Stanford  M.  Bull. — Stanford  University  Medical  Bul- 
letin. 

Siidd.   Apoth.-Ztg. — Suddeutsche   Apotheker-Zeitung. 

Surg.  Clinics  N.  America — Surgical  Clinics  of  North 
America. 

Surg.  Gynec.  Obst. — Surgery,  Gynecology  and  Ob- 
stetrics with  International  Abstract  of  Surgery. 

Surgery — Surgery. 

Texas  Repts.  Biol.  Med. — Texas  Reports  on  Biology 
and  Medicine. 

Texas  State  J.  Med. — Texas  State  Journal  of  Medi- 
cine. 

Ther.  Geg. — Therapie  de  Gegenwart. 

Therap.  Gaz. — Therapeutic  Gazette. 

Therap.  Halbmonatsh. — Therapeutische  Halbmonat- 
shefte. 

Therap.  Monatsh. — Therapeutische  Monatshefte. 

Tierdrztl.  Rundsch. — Tier'arztliche  Rundschau. 

Tohoku  J.  Exp.  Med. — Tohoku  Journal  of  Experi- 
mental Medicine. 

Trade  Corres. — Trade  Correspondence  of  the  Food 
and  Drug  Administration. 

Trans.  A.  Am.  Phys. — Transactions  of  the  Association 
of  American  Physicians. 

Trans.  Am.  Acad.  Ophth. — Transactions  of  the  Ameri- 
can Academy  of  Ophthalmology  and  Oto- 
laryngology. 

Trans.  Am.  Inst.  Chem.  Engrs. — Transactions  of  the 
American  Institute  of  Chemical  Engineers. 

Trans.  Am.  Laryng.  Rhin.  Otol.  Soc. — Transactions 
of  the  American  Laryngological,  Rhinological  and 
Otological  Society. 


Trans.  Am.  Neurol.  A. — Transactions  of  the  American 
Neurological  Association. 

Trans.  Chem.  Soc. — Transactions  of  the  Chemical 
Society  of  London. 

Trans.  Roy.  Soc.  Trop.  Med.  Hyg. — Transactions 
of  the  Royal  Society  of  Tropical  Medicine  and 
Hygiene. 

Trans.  South.  Surg.  Gynec.  A. — Transactions  of  the 
Southern  Surgical  and  Gynecological  Association. 

Trans.  Stud.  Coll.  Phys. — Transactions  and  Studies  of 
the  College  of  Physicians  of  Philadelphia. 

Trop.  Dis.  Bull. — Tropical  Diseases  Bulletin. 

U.  S.  Armed  Forces  M.  J. — United  States  Armed 
Forces  Medical  Journal. 

U.  S.  Army  Vet.  Bull. — United  States  Army  Veteri- 
nary Bulletin. 

U.S.D. — The  United  States  Dispensatory. 

U.S.D.A.  Farmers'  Bull. — United  States  Department 
of  Agriculture  Farmers'  Bulletin. 

U.S.D.A.  Leaflet. — United  States  Department  of  Agri- 
culture Leaflet. 

US.D.A.  Yearbook — United  States  Department  of 
Agriculture  Yearbook. 

U.  S.  Nav.  M.  Bull—  United  States  Naval  Medical 
Bulletin. 

U.SJP. — The  United  States  Pharmacopeia,  Fifteenth 
Revision. 

Ugeskr.  f.  laeger — Ugeskrift  for  laeger. 

Union  med.  Canada — Union  medicale  du  Canada. 

Univ.  Hosp.  Bull.  Ann  Arbor — University  Hospital 
Bulletin  (Ann  Arbor). 

Univ.  Mich.  M.  Bull. — University  of  Michigan  Medical 
Bulletin. 

Univ.  Penn.  Bull.  Vet.  Ext.  Quart. — University  of 
Pennsylvania  Bulletin  Veterinary  Extension  Quar- 
terly. 

Univ.  Penn.  M.  Bull. — University  of  Pennsylvania 
Medical  Bulletin. 

Upsala  lakaref.  fdrh. — Upsala  lakareforenings  for- 
handlingar. 

Urol.  Cutan.  Rev. — Urologic  and  Cutaneous  Review. 

Ven.  Dis.  Inform. — Venereal  Disease  Information. 

Vet.  Bull.  Lederle — Veterinary  Bulletin  (Lederle). 

Vet.  J. — Veterinary  Journal. 

Vet.  Med. — Veterinary  Medicine. 

Vet.  Rec. — The  Veterinary  Record. 

Vierteljahrsschr.  prakt.  Pharm. — Vierteljahrsschrift 
fiir  praktische  Pharmazie.  (Merged  into  Arch. 
Pharm.) 

Virchows  Arch.  path.  Anat. — Virchows  Archiv  fiir 
pathologische  Anatomie  und  Physiologie  und  fiir 
klinische  Medizin. 

Virginia  Med.  Month. — Virginia  Medical  Monthly. 

Vlaam's  Diergeneesk.  Tijdschr. — Vlaam's  Diergenees- 
kunde  Tijdschrift. 

War  Med. — War  Medicine. 

West.  J.  Surg.  Obst.  Gyn. — Western  Journal  of  Sur- 
gery, Obstetrics  and  Gynecology. 

West  Virg.  M.  J. — West  Virginia  Medical  Journal. 

Wien.  Chem.-Ztg. — Wiener  Chemiker-Zeitung. 

Wien.  klin.  Wchnschr. — Wiener  klinische  Wochen- 
schrift. 

Wien.  med.  Bl. — Wiener  medizinische  Blatter.  (Now 
Med.  Bl.) 

Wien.  tierdrztl.  Monatsschr. — Wiener  tierarztliche 
Monatsschrift. 

Wisconsin  Exp.  Sta.  Ann.  Rep.  Bull. — Wisconsin  Ex- 
periment Station  Annual  Report  Bulletin. 

Wisconsin  M.  J. — Wisconsin  Medical  Journal. 

Yale  J.  Biol.  Med. — Yale  Journal  of  Biology  and 
Medicine. 

Year-book  Pharm. — Year-book  of  Pharmacy  and 
Transactions  of  British  Pharmaceutical  Confer- 
ence. 

Zentralbl.  Bakt. — Zentralblatt  fiir  Bakteriologie, 
Parasitenkunde  und  Infektionskrankheiten. 


ABBREVIATIONS 


XVII 


Zentralbl.  Chir. — Zentralblatt  fur  Chirurgie. 
Zentralbl.  Gyntik. — Zentralblatt  fur  Gynakologie. 
Zentralbl.    Haut-Geschlechtskrank. — Zentralblatt    fur 

Haut-   und   Geschlechtskrankheiten   sowie  deren 

Grenzgebiete. 
Zentralbl.  inn.  Med. — Zentralblatt  fiir  innere  Medizin. 
Ztschr.     anal.     Chem. — Zeitschrift     fiir     analytische 

Chemie. 
Ztschr.  Biol. — Zeitschrift  fiir  Biologic 
Ztschr.  exp.  Path.  Titer. — Zeitschrift  fiir  experimen- 

telle  Pathologie  und  Therapie. 
Ztschr.  ges.  exp.  Med. — Zeitschrift  fur  die  gesamte  ex- 

perimentelle  Medizin. 
Ztschr.     ges.     Neurol.     Psych. — Zeitschrift     fiir     die 

gesamte  Neurologie  und  Psychiatric 
Ztschr.  Hyg.   Infektionskr. — Zeitschrift   fiir   Hygiene 

und  Infektionskrankheiten. 
Ztschr.  Immun.  exp.  Ther. — Zeitschrift  fiir  Immuni- 

tatsforschung  und  experimentelle  Therapie. 


Ztschr.  Infektionskr. — Zeitschrift  fiir  Infektionskrank- 
heiten, parasitare  Krankheiten  und  Hygiene  der 
Haustierc 

Ztschr.  Kinderh. — Zeitschrift  fiir  Kinderheilkunde. 

Ztschr.  klin.  Med. — Zeitschrift  fiir  klinische  Medizin. 

Ztschr.  Kreislauf. — Zeitschrift  fiir  Kreislaufforschung. 

Ztschr.  Laryng.  Rhin. — Zeitschrift  fiir  Laryngologie, 
Rhinologie,  Otologie  und  ihre  Grenzgebiete. 

Ztschr.  Naturforsch. — Zeitschrift  fiir  Naturforschung. 

Ztschr.  physiol.  Chem. — Zeitschrift  fiir  physiologische 
Chemie. 

Ztschr.  Untersuch.  Nahr.  Genussm. — Zeitschrift  fiir 
Untersuchung  der  Nahrungs-  und  Genussmittel, 
sowie  der  Gebrauchsgegenstande.  (Now  Ztschr. 
Untersuch.  Lebensm.) 

Ztschr.  Untersuch.  Lebensm. — Zeitschrift  fiir  Unter- 
suchung der  Lebensmittel. 

Ztschr.  Vitaminjorsch. — Zeitschrift  fiir  Vitaminfor- 
schung. 


THE   DISPENSATORY 

OF 

THE    UNITED    STATES 


PART  ONE:  Drugs  recognized  by  The  United  States 

Pharmacopeia,  British  Pharmacopoeia,  International 

Pharmacopoeia  or  The  National  Formulary 


ACACIA.    U.S.P.,  B.P. 

Gum  Arabic,   [Acacia] 

"Acacia  is  the  dried  gummy  exudate  from  the 
stems  and  branches  of  Acacia  Senegal  (Linne) 
Willdenow,  or  of  other  related  African  species  of 
Acacia  (Fam.  Leguminosa) ."  U.S. P.  The  B.P. 
definition  is  the  same  except  that  it  does  not 
specify  the  geographical  origin. 

Gum  Acacia.  Acaciae  Gurami;  Gummi  Africanum;  Gummi 
Mimosae;  Gummi  Arabicum.  Fr.  Gomme  arabique;  Gomme 
de  Senegal.  Ger.  Arabisches  Gummi;  Akazien  Gummi; 
Senegalgummi.  It.  Gomma  Arabica;  Gomma  del  Senegal. 
Sp.    Goma   de   acacia;    Goma  Ardbiga;   Goma   del   Senegal. 

The  name  Acacia  was  employed  by  the  ancient 
Greeks  to  designate  the  gum  tree  of  Egypt,  and 
has  been  appropriately  applied  to  the  genus  in 
which  that  plant  is  included.  Gum  Arabic  is  re- 
corded by  Herodotus  (5th  century  B.C.)  as  being 
used  by  the  ancient  Egyptians  as  an  adhesive.  Its 
use  in  medicine  is  mentioned  in  several  of  the 
Egyptian  papyri.  Hippocrates  refers  to  it  in  medi- 
cal works  published  between  450-350  B.C. 

The  genus  Acacia  includes  more  than  500  spe- 
cies of  tropical  trees  and  shrubs,  many  of  which 
have  been  of  considerable  economic  importance 
as  sources  of  gums,  tannins,  timber,  dyes  and 
perfumes.  The  Ark  of  the  Covenant  and  the 
furniture  of  the  Tabernacle  are  said  to  have  been 
made  from  timber  yielded  by  Acacia  Seyal,  the 
Shittim  wood  tree  of  the  Bible.  The  same  wood 
was  made  into  coffins  for  the  burial  of  the 
Egyptian  kings. 

The  acacias  thrive  in  the  forests  of  northern 
Africa,  occupying  a  zone  stretching  across  the 
continent  from  Abyssinia  in  the  east  to  Senegal 
in  the  west  and  chiefly  between  the  12  th  and  13  th 
degree  of  latitude.  The  most  important  of  the 
gum-yielding  acacias  is  the  official  A.  Senegal 
(Linne)  Willd.  This  is  a  small  tree  rarely  exceed- 
ing a  height  of  6  m.,  with  a  grayish  bark,  bipin- 
nate  leaves,  dense  spikes  of  small  yellow  flowers, 
and  broad  pods  containing  5  or  6  seeds.  It  forms 
large  forests  in  western  Africa,  north  of  the  river 
Senegal,  and  is  abundant  in  eastern  Africa,  Khor- 


1 


dofan,  and  southern  Nubia.  It  is  known  by  the 
natives  of  Senegambia  as  Verek  and  of  Khordofan 
as  Hashab. 

Nearly  all  species  of  acacia  growing  in  Africa 
yield  gum.  The  commercial  Somali  gum,  which  is 
usually  of  fair  quality,  is  yielded  by  A.  glauco- 
phylla  Steud.  and  A.  abyssinica  Hochst.,  shrubs 
growing  in  Abyssinia  and  the  Somali  country. 
The  following  species  yield  a  gum  having  a  brown- 
ish or  reddish  color,  and  hence  are  less  valuable, 
viz.,  African  A.  arabica  Willd.  (Amrad  gum),  A. 
stenocarpa  Hochst.  ex  A.  Rich.,  A.  Seyal  Del.  and 
A.  Ehrenbergiana  Hayne.  It  would  appear  from 
the  studies  of  Rangaswami  {Indian  J.  Pharm., 
1942,  4,  128)  that  the  pale  yellow  gum  from 
A.  arabica  produced  in  S.  India  nearly  approaches 
that  of  A.  Senegal  in  quality  and  could  be  used 
as  a  substitute  for  it.  Inferior  gums  are  yielded 
also  by  the  following:  A.  horrida  Willd.,  which 
furnishes  the  so-called  Cape  gum,  distinguished 
by  being  very  brittle  and  yielding  a  less  adhesive 
mucilage.  Talca  or  Sennarr  gum  is  derived  from 
A.  Seyal  Delile  and  A.  stenocarpa  Hochst.  ex  A. 
Rich.  This  gum  has  a  greenish  tinge  and  yields 
a  ropy  mucilage.  Amritsar  gum  is  obtained  from 
A.  modesta  Wall.  It  occurs  in  large  brown  tears 
and  like  A.  arabica  is  used  in  calico  printing. 
Mogadore  gum,  derived  from  A.  gummi f era 
Willd.,  occurs  in  dark  brown  tears  which  are  little 
fissured.  Australian  gum  has  usually  a  reddish 
color,  said  to  be  due  to  the  presence  of  tannin, 
although  some  specimens  are  light  in  color  and 
scarcely  distinguishable  from  acacia.  This  gum  is 
also  called  Wattle  gum  or  Australian  gum,  and  is 
derived  from  the  Golden  Wattle  Acacia  (A. 
pycnantha  Benth.),  a  shrub  growing  in  southern 
Australia.  Lutz  (/.  pharm.  chim.,  1942,  9:2,  49) 
gives  Acacia  decurrens  Willd.  var.  mollissima 
Willd.  as  the  source  of  Wattle  Gum.  However, 
the  term  "Wattle"  is  used  for  any  one  of  various 
species  of  Acacia  of  Australia,  Tasmania  and 
S.  Africa  which  are  valued  for  their  gum,  bark  or 
wood. 

The  astringent  bark  and  unripe   fruit   of   the 


Acacia 


Part  I 


acacia  contain  both  tannic  and  gallic  acids.  The 
dried  juice  of  the  pod  was  used  by  the  ancient 
Greeks;  and  an  extract  is  still  sold  in  the  bazaars 
of  India  under  the  name  of  Akakia. 

The  gum  of  the  acacias  exudes  spontaneously 
from  cracks  in  the  bark,  and  hardens  on  exposure; 
but  in  commercial  production  incisions  are  usually 
made  in  order  to  facilitate  the  exudation.  The 
gum  is  said  also  to  be  found  immediately  under 
the  bark,  where  it  is  sometimes  collected  in 
regular  cavities.  It  is  formed  within  the  plant  by 
metamorphosis  of  the  cells  of  the  inner  bark. 
The  tissues  involved  are  chiefly  those  of  the 
sieve  and  the  cambium.  The  formation  of  the  gum 
is  believed  to  be  a  pathological  process,  as  gum- 
mosis  develops  more  largely  upon  the  wounding 
of  the  trees  and  their  infection  by  bacteria  and 
other  parasites.  The  investigations  of  Smith  tend 
to  show  that  all  vegetable  gums  are  of  bacterial 
origin  and  that  the  differences  in  the  several  gums 
are  due  to  the  differences  in  the  nature  of  the 
bacteria  producing  them.  (Proc.  Linn.  Soc.  N.  S. 
Wales,  1904,  p.  217.)  For  further  discussion  of 
the  origin  of  acacia  gum  see  Tschirch,  "Hand- 
buch  der  Pharmakognosie,"  and  Greenish,  "Mate- 
ria Medica,"  4th  ed. 

The  trees  are  not  tapped  for  gum  until  they 
are  about  six  years  old.  Annual  yields  from  188 
to  2856  Gm.  in  young  trees  and  from  379  to  6754 
Gm.  in  large  trees  have  been  reported.  The  aver- 
age annual  yield  of  gum  from  young  trees  is  about 
900  Gm.  and  from  old  trees  over  2  kilos. 

Commercial  History  and  Varieties. — 
There  are  two  principal  commercial  varieties  of 
gum  arabic:  1.  The  Kordofan,  Gedaref  or  Arabian 
Gum,  and  2.  the  Senegal  or  West  African  Gum, 
both  of  these  being  derived  from  A.  Senegal.  The 
former  of  these  has  the  finer  commercial  qualities, 
being  nearly  white  or  faint  yellowish-white  and 
yielding  a  more  or  less  transparent  viscid  muci- 
lage. 

Kordofan  or  Arabian  Gum. — This  is  the 
finest  variety  of  gum  arabic  obtainable.  It  is 
gathered  in  the  Kordofan  province  of  the  Sudan. 
It  was  formerly  the  only  kind  designated  as  gum 
arabic  and  entered  commerce  almost  exclusively 
through  Egypt. 

It  now  occurs  in  two  sub-varieties  designated 
as  "Bleached  Kordofan  Gum"  and  "Natural  Kor- 
dofan Gum."  The  bleached  variety  is  the  most 
highly  esteemed  and  occurs  in  white  or  weak  yel- 
low angular  fragments  or  ovoid  tears  the  outer 
surfaces  of  which  bear  numerous  cracks.  The 
natural  variety  differs  from  the  former  by  being 
more  transparent,  owing  to  fewer  cracks,  and  in 
being  more  deeply  yellow  or  pinkish  in  color. 

During  the  conquest  of  the  Sudan  by  Anglo- 
Egyptian  forces  in  1908,  a  railway  was  built  from 
Egypt  to  Khartoum  in  the  Sudan,  and  since  ex- 
tended from  Khartoum  to  El  Obeid  and  Gedaref, 
which  opened  up  large  areas  of  acacia  country  in 
which  the  gum  is  now  collected.  The  chief  Egyp- 
tian Sudan  market  is  at  El  Obeid,  the  shipping 
companies  having  their  main  offices  at  Khartoum 
about  500  miles  distant.  The  finest  Egyptian  gum 
consists  of  large  roundish  or  smaller  more  or  less 
irregular  fragments,  transparent  but  usually 
rendered  opaque  upon  the  surface  by  innumerable 


minute  fissures.  For  information  concerning 
method  of  collection  see  U.S.D.,  24th  ed.,  p.  2. 
Talca  or  Talha  gum,  from  A.  stenocarpa  and 
A.  Seyal,  is  exceedingly  brittle,  and  usually  semi- 
pulverulent.  It  is  a  mixture  of  nearly  colorless 
and  brownish  gums,  is  exported  at  Alexandria,  and 
is  sometimes  termed  gam  savakin  or  Suakin  gum. 

Senegal  or  West  African  Gum. — This  com- 
mercial variety  ranks  second  to  the  Kordofan 
gum.  It  is  derived  front  A.  Senegal  and  other 
species  of  Acacia  growing  in  the  Sudan  and 
Senegal.  It  yields  a  good  adhesive  mucilage  and 
is  valuable  for  technical  purposes.  Some  of  the 
best  qualities  of  Senegal  gum  are  also  adapted  for 
certain  pharmaceutical  uses.  It  was  introduced 
into  Europe  by  the  Dutch.  The  French  afterwards 
planted  a  colony  on  the  western  coast  of  Africa, 
and  took  possession  of  the  trade.  The  dry  winds, 
which  prevail  after  the  rainy  season,  cause  the 
bark  to  crack;  the  juice  flows  out  and  hardens  in 
masses.  It  is  claimed  that  the  exudation  is  also 
largely  caused  by  a  parasitic  plant,  Loranthus 
AcacicB  Zucc,  the  gummy  exudation  freely  oozing 
out  at  the  point  where  the  parasite  penetrates  the 
bark.  Senegal  gum  is  usually  in  roundish  or  oval 
unbroken  tears,  or  in  straight  or  curled  cylindrical 
pieces  of  various  sizes,  in  the  finest  grades  whitish 
or  colorless,  but  generally  yellowish,  reddish,  or 
brownish-red.  The  pieces  are  generally  larger  than 
those  of  Kordofan  gum,  less  brittle,  fissured,  and 
pulverizable,  and  break  with  a  more  conchoidal 
fracture.  Vermiform  tears  are  usually  present  and 
aid  in  diagnosing  this  variety.  It  is  shipped  from 
the  Senegal  river  to  France  and  the  United  States. 

The  total  imports  of  acacia  into  this  country 
during  1952  were  over  20  million  pounds,  mostly 
from  Sudan,  Nigeria,  East  Africa  and  India. 

Impurities  and  Adulterations. — As  gum 
arabic  is  usually  collected  in  huge  piles  at  Khar- 
toum, Gedaref,  etc.,  before  being  shipped  to  Port 
Sudan  the  sand  and  impurities  are  likely  to  sift 
to  the  bottom.  As  a  consequence  the  first  orders 
will  be  filled  with  the  cleaner  article,  while  the 
latter,  containing  the  siftings,  may  run  as  high 
as  4  per  cent  of  ash.  The  inferior  grades  are  often 
mixed  with,  or  substituted  for,  the  better  kinds, 
especially  in  powder. 

The  chief  adulterant  and  substitute  for  acacia 
within  recent  years  has  been  Mesquite  gum,  from 
Prosopis  chilensis  (Molina)  Stuntz  (Fam.  Legu- 
minosce),  a  plant  indigenous  to  Mexico.  It  occurs 
in  brownish  to  reddish-brown  tears  of  variable 
size  and  differs  from  acacia  in  not  precipitating 
from  its  aqueous  solution  when  solutions  of  ferric 
chloride,  lead  subacetate  or  sodium  borate  are 
added. 

Description. — "Unground  Acacia  occurs  in 
spheroidal  tears  up  to  32  mm.  in  diameter  or  in 
angular  fragments  of  white  to  yellowish  white 
color.  It  is  translucent  or  somewhat  opaque  from 
the  presence  of  numerous  minute  fissures;  very 
brittle,  the  fractured  surface  glassy  and  occa- 
sionally iridescent.  It  is  almost  odorless  and  has  a 
mucilaginous  taste. 

"Flake  Acacia  occurs  in  white  to  yellowish 
white,  thin  flakes,  appearing  under  the  microscope 
as  colorless,  striated  fragments. 

"Powdered  Acacia  is  white  to  yellowish  white. 


Part  I 


Acacia 


It  occurs  in  angular  microscopic  fragments  with 
but  slight  traces  of  starch  or  vegetable  tissues 
present. 

"Granular  Acacia  is  Acacia  reduced  to  fine 
granules.  It  is  white  to  pale  yellowish  white. 
Under  the  microscope  it  appears  as  colorless, 
glassy,  irregularly  angular  fragments  up  to  100  m* 
in  thickness,  some  of  which  exhibit  parallel  linear 
streaks. 

"Solubility. — One  Gm.  of  Acacia  dissolves  in 
2  ml.  of  water;  the  resulting  solution  flows 
readily  and  is  acid  to  litmus.  It  is  insoluble  in 
alcohol."  U.S.P. 

Acacia  is  insoluble  in  ether,  and  in  oils.  In  22 
per  cent  alcohol  the  solubility  is  57  Gm.  in  100 
ml.;  in  40  per  cent  alcohol,  10  Gm.  in  100  ml.; 
in  50  per  cent  alcohol,  4  Gm.  in  100  ml. 

Standards  and  Tests. — Identification. — A 
flocculent,  or  curdy,  white  precipitate  is  produced 
immediately  when  0.2  ml.  of  diluted  lead  subace- 
tate  T.S.  is  added  to  10  ml.  of  a  1  in  50,  cold, 
aqueous  solution  of  acacia.  Total  ash. — Not  over 
4  per  cent.  Acid-insoluble  ash. — Not  over  0.5  per 
cent.  Water. — Not  over  15  per  cent.  Optical  rota- 
tion.— A  1  in  10  solution  is  only  slightly  levorota- 
tory.  Insoluble  residue. — A  mixture  of  5  Gm.  of 
acacia,  100  ml.  distilled  water  and  10  ml.  of 
diluted  hydrochloric  acid  boiled  gently  for  15 
minutes  yields  a  residue  not  exceeding  50  mg. 
Starch  or  dextrin. — Iodine  T.S.  does  not  give  a 
bluish  or  reddish  color  with  a  1  in  50  aqueous 
solution  of  acacia,  previously  boiled  and  cooled. 
Tannin-bearing  gums. — No  blackish  coloration  or 
precipitate  is  produced  when  0.1  ml.  of  ferric 
chloride  T.S.  is  added  to  10  ml.  of  a  1  in  50 
aqueous  solution  of  acacia.  U.S.P. 

The  B.P.  specifies  the  following  identification 
tests  for  acacia:  (1)  A  flocculent  white  precipitate 
is  produced  on  adding  a  strong  solution  of  lead 
subacetate  to  a  1  in  50  solution  of  acacia.  (2) 
A  deep  blue  color  is  produced  on  adding  0.5  ml.  of 
hydrogen  peroxide  solution  and  0.5  ml.  of  a  1  in 
100  solution  of  benzidine  (in  90  per  cent  alcohol) 
to  a  solution  of  250  mg.  of  acacia  in  5  ml.  of 
water,  the  mixture  being  allowed  to  stand.  (3) 
Particles  of  powdered  acacia  mounted  in  solution 
of  ruthenium  red  show  no  red  color  when  ex- 
amined microscopically  (distinction  from  agar  and 
from  sterculia).  (4)  No  precipitate  is  produced  on 
adding  0.2  ml.  of  a  1  in  5  solution  of  lead  acetate 
to  10  ml.  of  a  1  in  50  solution  of  acacia  (dis- 
tinction from  agar  and  from  tragacanth).  (5)  A 
mixture  of  100  mg.  of  powdered  acacia  and  1  ml. 
of  0.02  N  iodine  does  not  acquire  a  crimson  or 
olive-green  color  (distinction  from  agar  and  from 
tragacanth). 

Gum  arabic  undergoes  no  change  on  aging,  if 
kept  in  a  dry  place.  Its  concentrated  aqueous 
solution  remains  stable  for  a  considerable  time, 
but  ultimately  becomes  sour,  acid  being  formed. 
The  tendency  to  sour  is  said  to  be  increased  by 
using  hot  water  in  making  the  solution. 

Constituents. — Acacia  consists  principally  of 
the  calcium,  magnesium  and  potassium  salts  of  a 
polysaccharide  known  as  arabic  acid,  sometimes 
called  arabin.  On  hydrolysis  with  dilute  acid, 
arabic  acid  yields  L-arabinose,  L-rhamnose, 
D-galactose,   and  an   aldobionic   acid   containing 


D-glucuronic  acid  and  D-galactose  in  glycosidal 
combination.  An  oxidase-type  enzyme  is  present 
in  acacia,  and  it  is  claimed  that  diastase  is  also  a 
constituent. 

Incompatibilities. — Bourquelot  (/.  phartn. 
chim.,  1904,  19,  473,  474)  reported  that  acacia 
contains  an  oxidase-type  enzyme  which  may 
render  it  unsuitable  for  use  in  pharmaceutical 
preparations  which  contain  easily  oxidized  active 
constituents.  Thus,  Kedvessy  (Chem.  Abs.,  1943, 
37,  4531)  reported  that  the  vitamin  A  content  of 
cod  liver  oil  emulsions  made  with  acacia  decreased 
54  per  cent  in  three  weeks.  Griffiths  et  al. 
{Analyst,  1933,  58,  65),  on  the  other  hand,  found 
that  such  emulsions  can  be  kept  for  at  least  four 
months  without  serious  loss  of  vitamin  A  if  stored 
in  well-filled,  amber  glass  bottles  and  kept  in  the 
dark.  Substances  stated  to  be  incompatible  with 
acacia  include  aminopyrine,  pyrogallol,  morphine, 
vanillin,  phenol,  thymol,  carvol,  a-  and  (5-naphthol, 
pyrocatechol,  guaiacol,  cresols,  creosol,  eugenol, 
acetyleugenol,  apomorphine,  eserine,  epinephrine, 
isobarbaloin,  caffeotannic  acid,  gallic  acid  and 
tannin.  Kieft  (Pharm.  Weekblad,  1939,  76,  1133) 
recommended  heating  acacia  at  103°  to  105°  C. 
as  the  best  method  for  destroying  its  oxidase 
enzyme.  The  oxidizing  action  of  acacia  mucilage 
may  be  destroyed  by  heating  at  100°  C. 

Acacia  is  also  incompatible  with  strongly  alco- 
holic liquids,  solutions  of  ferric  chloride  and  lead 
subacetate,  and  strong  solutions  of  sodium  borate. 

Uses. — Sodium  chloride  injection  is  of  little 
practical  value  in  the  treatment  of  low  blood  pres- 
sure from  hemorrhage  or  surgical  shock  because 
it  escapes  so  rapidly  from  the  blood  vessels.  This 
characteristic  is  generally  attributed  to  its  non- 
colloid  character  and  in  1917  Bayliss  suggested 
the  use  of  a  7  per  cent  solution  of  acacia  to  im- 
part the  necessary  colloid  material.  Although  the 
method  has  received  some  favorable  reports  (for 
literature  see  Maytum  and  Magath,  J.A.M.A., 
1932,  99,  2251)  the  availability  of  blood  plasma 
and  plasma  expanders,  such  as  dextran  and 
polyvinylpyrrolidone,  led  to  an  almost  complete 
abandonment  of  the  procedure. 

In  1933  Hartmann  and  co-workers  recom- 
mended intravenous  injection  of  acacia  solutions 
to  relieve  the  edema  of  certain  types  of  nephrosis, 
on  the  theory  that  the  edema  is  due  to  a  dis- 
turbance of  the  cclloid  pressure  of  blood  brought 
about  by  a  diminution  in  its  protein  content. 
There  has  been  considerable  difference  of  opinion 
as  to  whether  the  final  results  are  beneficial  or 
injurious.  Large  intravenous  doses  of  acacia  in 
animals  (15  to  47  Gm.  per  kilogram  in  dogs) 
produce  toxic  effects,  including  reduction  of  eryth- 
rocytes, hemoglobin  and  hematocrit,  hastened 
sedimentation  of  erythrocytes,  transitory  leuko- 
penia and  reduction  of  serum  proteins,  especially 
of  serum  albumin  (Hueper,  Am.  I.  Path.,  1942, 
18,  895).  Tissue  examination  shows  enlargement 
and  thickening  of  the  liver.  The  parenchymal 
cells  around  the  central  vein  and  in  the  periportal 
areas  stain  lightly,  appear  distended  and  contain 
a  vacuolated  cytoplasm  (foam  cells)  which  does 
not  take  the  special  stains  used  for  fat,  glycogen, 
mucin  or  amyloid  and  is  probably  acacia.  Infiltra- 
tion  with   inflammatory    cells   is   minimal.   The 


Acacia 


Part  I 


foam  cells  persist  for  2  years  or  more  and  serum 
albumin  remains  depressed  although  the  level  rises 
slowly.  Similar  foam  cells  are  less  numerous  in 
the  spleen  and  the  convoluted  tubules  of  the 
kidney. 

However,  in  patients  who  had  received  as  much 
as  210  Gm.  (3.7  Gm.  per  kilo)  of  acacia,  as  long 
as  3  years  or  as  recently  as  3  weeks  before  death 
due  to  other  causes,  no  such  histologic  changes 
were  observed.  Patients  given  60  Gm.  of  acacia 
in  the  treatment  of  shock  a  few  days  before  death 
showed  no  foam  cell  changes  (Smalley,  Binger, 
Bollman  and  Power,  Arch.  Int.  Med.,  1945,  76, 
39).  Chemical  analyses  demonstrate  about  20  per 
cent  of  the  acacia  in  the  urine  during  the  first 
few  days;  some  acacia  appears  in  the  feces  and 
about  20  per  cent  is  stored  in  the  liver;  only  traces 
are  found  in  other  tissues.  A  decrease  in  serum 
albumin  concentration  associated  with  an  increase 
in  plasma  volume  ^ccurs  and  returns  toward 
normal  after  discontinuing  the  injections  (Yuile 
and  Knutti,  /.  Exp.  Med.,  1939,  70,  605).  A 
variety  of  tests  of  liver  function  reveal  no  impair- 
ment. In  edematous  patients,  the  urinary  excre- 
tion of  sodium  chloride  and  water  is  increased. 

Smalley  and  Binger  (J.A.M.A.,  1944,  126,  532) 
reported  on  the  condition  of  patients  2  to  7  years 
after  the  intravenous  injection  of  acacia.  They 
treated  109  patients  with  the  nephrotic  syndrome 
in  the  course  of  chronic  glomerulo-nephritis. 
These  edematous  patients  with  hypoproteinemia 
and  albuminuria  were  treated  with  a  low-salt, 
high-protein  (75-125  Gm.  daily)  diet,  1  to  1.5 
liters  of  fluid  daily  and  3  Gm.  of  potassium  nitrate 
3  times  a  day.  Edema  did  not  subside  in  these 
cases.  Then,  500  ml.  of  a  6  per  cent  solution  of 
pure  acacia  (30  Gm.)  in  0.06  per  cent  sodium 
chloride  in  distilled  water  was  given  intravenously 
on  alternate  days  for  3  doses.  After  the  third  in- 
jection the  concentration  of  acacia  in  the  blood 
was  about  2  Gm.  per  100  ml.;  a  year  later  0.1  Gm. 
per  100  ml.  remained.  After  2  to  7  years,  12  cases 
were  not  traced;  72  cases  were  alive  and  49  were 
performing  a  full  day's  work,  21  were  working 
part-time  and  2  were  bedfast;  the  remaining  25 
cases  were  dead  of  uremia,  hypertension  or  cardiac 
failure  but  of  these  20  had  lost  their  edema  and 
12  had  lived  2  years  and  5  for  4  years  after  treat- 
ment with  acacia.  No  evidence  of  renal  or  hepatic 
damage  was  observed  in  these  patients  and,  in 
fact,  many  cases  showed  fewer  erythrocytes,  leu- 
kocytes and  casts  in  the  urine  and  decreased  al- 
buminuria as  the  edema  subsided.  In  especially 
resistant  cases,  injection  of  mercurial  diuretics  on 
alternate  days,  between  the  acacia  injections,  was 
found  to  be  effective  and  safe.  Most  patients 
received  90  Gm.  of  acacia  but,  if  necessary,  as 
much  as  200  Gm.  appears  to  be  safe.  Larger  doses 
produce  the  deleterious  effects  already  described 
(Falkenstein  and  Jackson,  /.  Pediatr.,  1940,  16, 
700). 

Reactions  during  injection  of  acacia  occurred 
in  12  of  the  109  cases  consisting  of  cold  extremi- 
ties, flushing  of  the  face,  chill,  nausea,  vomiting, 
dyspnea  and  urticaria.  Epinephrine  effectively 
controlled  or  prevented  these  reactions. 

Industrial  exposure  to  acacia,  especially  as  an 
"offset  spray"  in  printing,  may  cause  asthmatic 


seizures.  Acacia  contains  sufficient  protein  nitro- 
gen to  serve  as  an  antigen  (Bohner,  Sheldon  and 
Trenis,  /.  Allergy,  1941,  12,  290). 

In  plastic  surgery,  a  50  per  cent  acacia  "glue" 
has  been  employed  successfully  in  grafting  de- 
stroyed peripheral  nerves  (Klemme,  Woolsey  and 
deRezende,  J.A.M.A.,  1943,  123,  393). 

In  irritations  of  the  mouth  or  fauces,  a  small 
lump  or  lozenge  of  acacia  may  be  allowed  to  dis- 
solve slowly  in  the  mouth  for  its  demulcent  effect. 
The  hygroscopic  property  of  acacia  has  not  proved 
sufficiently  marked  in  the  intestine  to  serve  as  a 
hydrophilic  laxative  (Gray  and  Tainter,  Am.  J. 
Digest.  Dis.,  1941,8,  130). 

In  pharmacy,  acacia  is  extensively  used  in  the 
preparation  of  emulsions  (see  Emulsions,  Part  II), 
for  the  suspension  of  insoluble  substances  in  mix- 
tures, and  as  a  binding  agent  in  tablets,  pills  and 
troches.  For  the  preparation  of  emulsions  by  the 
Continental  method,  in  which  acacia  is  required 
to  be  mixed  with  the  oil,  preference  is  usually 
given  to  the  finely  powdered  form;  granulated 
acacia,  possibly  because  of  its  greater  content  of 
water,  dissolves  more  readily  in  water  with  less 
tendency  to  form  lumps  and  is  preferable  for  the 
preparation  of  aqueous  solutions.  As  a  general 
rule,  one  part  of  acacia  is  sufficient  for  the  emulsi- 
fication  of  four  parts  of  fixed  oil  or  two  parts  of 
volatile  oil.  S 

Off.  Prep.— Acacia  Mucilage  U.S.P.,  B.P.; 
Cod  Liver  Oil  Emulsion;  Liquid  Petrolatum 
Emulsion,  N.F.,  B.P.;  Compound  Chalk  Powder; 
Phenolphthalein  in  Liquid  Petrolatum  Emulsion, 
N.F.;  Compound  Powder  of  Tragacanth,  B.P. 

ACACIA  MUCILAGE.    U.S.P.  (B.P.) 

[Mucilago  Acaciae] 

B.P.    Mucilage  of    Acacia.    Mucilago    Gumrai    Arabici. 

Fr.    Mucilage   de  gomrae   arabique.    Gcr.    Gummischleim. 

It.  Mucillaggine  di  gomma  arabica.  Sp.  Mucilago  de 
goma  Arabiga. 

Place  350  Gm.  of  acacia,  in  small  fragments, 
in  a  graduated  bottle  having  a  wide  mouth  and  a 
capacity  not  much  more  than  1000  ml.  Wash  the 
drug  with  cold  purified  water,  allow  it  to  drain, 
and  add  enough  warm  purified  water,  in  which  2 
Gm.  of  benzoic  acid  has  been  dissolved,  to  make 
the  product  measure  1000  ml.  Stopper  the  bottle, 
lay  it  on  its  side,  rotate  it  occasionally,  and  when 
solution  has  been  effected  strain  the  mucilage. 
Acacia  mucilage  may  also  be  prepared  by  adding 
400  ml.  of  purified  water,  in  which  the  benzoic 
acid  has  been  dissolved  with  the  aid  of  heat,  to 
350  Gm.  of  powdered  or  granular  acacia  and 
triturating  until  the  acacia  is  dissolved;  sufficient 
purified  water  is  added  to  make  the  product  meas- 
ure 1000  ml.  U.S.P. 

"Caution. — Acacia  Mucilage  must  be  free  from 
mold  or  any  other  indication  of  decomposition." 
U.S.P. 

The  B.P.  mucilage  is  prepared  by  dissolving 
400  Gm.  of  acacia,  previously  washed  with  water, 
in  600  ml.  of  chloroform  water. 

Acacia  mucilage  does  not  keep  very  well. 
Though  many  suggestions  have  been  offered  for 
preserving  it,  none  appears  to  be  entirely  satis- 
factory. Generally,  addition  of  a  preservative  in- 
troduces potential  incompatibilities;   the   use   of 


Part  I 


Acetanilid 


chloroform  water,  as  directed  by  the  B.P.,  may  be 
objectionable  because  of  the  taste  it  gives  to  the 
preparation. 

Acacia  mucilage  is  employed  as  an  aid  in  sus- 
pending insoluble  substances  in  liquids,  as  an 
emulsifier,  and  as  a  pill  and  tablet  excipient.  Occa- 
sionally it  is  employed  for  its  demulcent  effect, 
the  average  dose  being  15  ml.  (approximately 
4  fluidrachms). 

Storage. — Preserve  "in  tight  containers." 
U.S.P. 

ACACIA  SYRUP.    U.S.P. 

[Syrupus  Acaciae] 

Syrupus  Gummi  (Gummosus);  Sirupus  Gummi  Arabici. 
Fr.  Sirop  de  gomme.  Ger.  Gummisirup.  It.  Sciroppo  di 
gomma  arabica.  Sp.  Jarabe  de  goma. 

Mix  100  Gm.  of  granulated  or  powdered  acacia, 
1  Gm.  of  sodium  benzoate,  and  800  Gm.  of 
sucrose;  add  425  ml.  of  purified  water,  mix,  and 
heat  the  mixture  on  a  water  bath  until  solution 
is  effected.  Cool,  remove  the  scum,  add  5  ml.  of 
vanilla  tincture  and  sufficient  purified  water  to 
make  the  product  measure  1000  ml.  Strain  if 
necessary.  U.S.P. 

This  demulcent  syrup  is  often  effective  in  mask- 
ing the  bitter  or  acid  taste  of  medicaments,  per- 
haps in  part  functioning  by  a  protective  colloid 
action.  A  dose  of  4  to  15  ml.  (approximately  1  to 
4  fluidrachms)  is  used. 

Storage. — Preserve  "in  tight  containers,  and 
avoid  excessive  heat."  U.S.P. 


ACETANILID. 

[Acetanilidum] 


N.F. 


NHC0CH3 


Antifebrin;  Phenylacetamide;  Acetylamidobenzene;  Mono- 
acetylaniline.  Fr.  Acetanilide.  Ger.  Azetanilid;  Acet- 
phenylamid.  Sp.  Acetanilida ;  Acetilfenilamina. 

Acetanilid,  introduced  into  medicine  in  1886  as 
antifebrin,  may  be  prepared  by  the  action  of 
acetic  anhydride,  acetyl  chloride,  or  glacial  acetic 
acid  on  aniline.  A  commercial  process  involves 
heating  glacial  acetic  acid  and  aniline  for  several 
hours  until  tests  show  the  absence  of  unreacted 
aniline.  The  crude  product  is  purified  by  re- 
crystallization  from  hot  water. 

Description. — "Acetanilid  occurs  as  white, 
shiny  crystals,  usually  in  scales,  or  as  a  white, 
crystalline  powder.  It  is  odorless,  and  is  stable  in 
air.  Its  saturated  solution  is  neutral  to  litmus 
paper.  One  Gm.  of  Acetanilid  dissolves  in  190  ml. 
of  water,  in  3.5  ml.  of  alcohol,  in  4  ml.  of  chloro- 
form, and  in  about  17  ml.  of  ether.  One  Gm. 
dissolves  in  20  ml.  of  boiling  water,  and  in  about 
0.6  ml.  of  boiling  alcohol.  It  is  soluble  in  glycerin. 
Acetanilid  melts  between  114°  and  116°."  N.F. 

Standards  and  Tests. — Identification. — (1) 
100  mg.  of  acetanilid  boiled  with  5  ml.  of  sodium 
hydroxide  T.S.  evolves  vapors  of  aniline;  addition 
of  several  drops  of  chloroform  and  further  heat- 
ing produces  phenyl  isocyanide,  a  poisonous  com- 
pound recognized  by  its  disagreeable  odor.  (2)  A 
white,  crystalline  precipitate  of  ^-bromoacet- 
anilid  forms  on  adding  a  few  drops  of  bromine 


T.S.  to  10  ml.  of  saturated  solution  of  acetanilid. 
Loss  on  drying. — Not  over  0.5  per  cent  on  drying 
over  sulfuric  acid  for  2  hours.  Residue  on  igni- 
tion.— Not  over  0.05  per  cent.  Readily  carboniz- 
able  substances. — A  solution  of  500  mg.  of  acet- 
anilid in  5  ml.  of  sulfuric  acid  has  no  more  color 
than  matching  fluid  A.  N.F. 

Incompatibilities. — Acetanilid  is  incompat- 
ible with  alkalies  (which  liberate  aniline)  and 
when  it  is  triturated  with  phenol,  resorcinol, 
chloral  hydrate,  acetylsalicylic  acid,  antipyrine, 
and  many  other  organic  drugs  it  forms  a  mixture 
which  liquefies.  With  ethyl  nitrite  spirit,  amyl 
nitrite,  or  with  acid  solutions  of  nitrites  a  yellow 
solution  is  produced  which  turns  to  red  upon 
standing.  In  acid  solutions  acetanilid  is  slowly 
hydrolyzed.  Bromides  and  iodides  form  with  acet- 
anilid a  precipitate.  Ferric  salts  produce  with  it  a 
red  color. 

Uses. — Acetanilid  possesses  analgesic  and 
antipyretic  properties,  and  is  today  used  in  medi- 
cine especially  for  the  former,  and  to  a  lesser 
extent  for  the  latter,  effect.  As  with  acetophenet- 
idin,  it  yields  in  the  system  principally  N-acetyl- 
/»-aminophenol,  to  which  the  therapeutic  utility 
of  the  compounds  is  apparently  attributable. 
From  70  to  90  per  cent  of  acetanilid  administered 
to  humans  appears  in  the  urine  as  conjugation 
derivatives,  with  sulfuric  acid  and  glucuronic  acid, 
of  />-aminophenol  and  its  N-acetyl  derivative 
(Greenberg  and  Lester,  /.  Pharmacol.,  1946,  88, 
87).  A  minor  fraction  of  acetanilid  deacetylates 
to  aniline  (ibid.,  1948,  94,  29). 

The  most  striking  actions  of  acetanilid  are  upon 
the  heat-regulating  mechanism  and  upon  pain 
perception.  The  maintenance  of  body  tempera- 
ture is  the  result  of  a  delicate  balance  between 
the  amount  of  heat  generated  in  the  system  by 
oxidation  and  that  which  is  utilized  or  dissipated. 
Antipyretics,  including  acetanilid,  have  little  if 
any  effect  on  production  of  heat;  their  action 
appears  to  be  that  of  increasing  dissipation  of  heat 
by  dilatation  of  cutaneous  blood  vessels  and  by 
increasing  the  degree  of  sweating.  There  is  differ- 
ence of  opinion  as  to  the  advisability  of  using 
antipyretic  drugs  to  lower  body  temperature  when 
it  is  elevated.  At  times  these  drugs  produce  such 
a  sudden  or  excessive  change  as  to  lead  to 
collapse.  The  need  for  antipyretic  drugs  has 
diminished  as  effective  chemotherapeutic  agents 
have  become  available. 

The  most  important  use  of  acetanilid  at  the 
present  time  is  for  the  relief  of  pain,  especially 
that  of  neuralgia,  whether  of  the  head  or  other 
portions  of  the  body.  While  it  will  usually  relieve 
even  severe  neuralgic  pains,  it  is  comparatively 
feeble  in  traumatic  conditions.  It  is  believed  that 
the  analgesic  effect  is  the  result  of  depression  of 
the  pain-perceiving  mechanism.  Hale  and  Grab- 
field  (/.  Pharmacol.,  1923,  21,  77),  in  experi- 
ments upon  men,  found  that  the  threshold  of 
perception  of  faradic  irritation  of  the  skin  was 
raised  about  30  per  cent.  Wolff,  Hardy  and 
Goodell  (/.  Clin.  Inv.,  1941,  20,  62)  reported  a 
similar  degree  of  reduction  in  the  perception  of 
pain  caused  by  radiant  heat.  The  analgesic  effect 
appeared  about  an  hour  after  oral  administration, 
and  persisted  for  2  to  3  hours.  Doses  larger  than 


Acetanilid 


Part  I 


300  mg.  did  not  increase  or  prolong  the  analgesic 
effect.  In  the  presence  of  pain  induced  by  a 
tourniquet  on  the  arm  which  obstructed  arterial 
flow  for  30  minutes,  acetanilid  induced  the  same 
decrease  in  the  sensitivity  to  the  discomfort 
caused  by  radiant  heat  on  the  forehead  as  it  did 
in  the  absence  of  pain  in  the  arm.  In  contrast 
morphine,  which  raised  the  threshold  about  70 
per  cent  without  pain  in  the  arm,  elevated  the 
threshold  (to  heat  on  the  forehead)  only  about 
30  to  40  per  cent  when  ischemic  pain  was  present 
in  the  arm.  Acetanilid  allayed  restlessness  and 
anxiety  more  effectively  than  did  300  mg.  of 
acetylsalicylic  acid.  Combinations  with  other 
analgesic  drugs  did  not  enhance  the  action  above 
that  of  the  most  effective  component.  Mullin  and 
Luckhardt  (Arch,  internal,  pharmacodyn.  therap., 
1937,  55,  112),  on  the  other  hand,  did  not  find 
acetanilid  to  produce  in  men  any  diminution  in 
the  perception  of  pressure  pain. 

Locally  acetanilid  is  mildly  antiseptic  and  to 
some  degree  anesthetic.  It  has  been  used  as  a 
dusting  powder  in  various  types  of  ulcers,  but  its 
use  is  not  free  from  danger  and  it  does  not  appear 
to  have  any  great  advantage  over  a  number  of 
other  safer  remedies  for  this  purpose.  H 

Toxicology. — The  freedom  with  which  acet- 
anilid and  allied  drugs  are  used  by  the  laity 
makes  the  subject  of  their  potential  danger  a 
matter  of  considerable  economic  as  well  as  hy- 
gienic importance.  Unfortunately,  much  that  has 
been  written  on  the  subject  has  been  in  the  spirit 
of  trying  to  establish  a  preconceived  opinion 
rather  than  to  discover  the  truth.  From  the  welter 
of  polemics,  certain  deductions  are  scientifically 
justified. 

In  ordinary  doses  acetanilid  has  no  demonstra- 
ble action  on  respiration  or  circulation  in  lower 
animals,  although  in  very  large  quantities  it  acts 
as  a  depressant  to  the  heart  (Higgins  and 
McGuigan,  /.  Pharmacol,  1933,  49,  466).  It 
appears  also  to  be  feebly  depressant  to  the  motor 
centers  in  the  cord. 

Acute  poisoning  (cyanosis,  prostration  and  col- 
lapse) is  rare.  The  acute  lethal  dose  of  acetanilid 
for  the  lower  animals  (see  Clark,  /.  Pharmacol., 
1940,  69,  280),  and  ordinarily  for  men,  is  so  large 
that  one  would  hardly  class  it  as  a  poison.  On  the 
other  hand,  there  have  been  several  deaths  from 
acute  acetanilid  poisoning,  one  from  as  little  as 
18  grains.  Several  of  these  deaths  occurred  dur- 
ing its  use  in  fever  and  it  is  well  known  that  a 
sudden  reduction  in  body  temperature  may  pro- 
duce circulatory  collapse.  The  common  custom 
of  adding  caffeine  to  acetanilid  mixtures  to  guard 
against  cardiac  depression  has  been  shown  by 
several  investigators  to  be  futile;  indeed  it  seems 
well  established  that  caffeine  increases  the  toxicity 
of  acetanilid  (see  Smith  and  Hambourger.  /. 
Pharmacol,  1935.  55,  200  and  1936,  57,  34).  The 
number  of  deaths  from  acetanilid  which  can  be 
ascribed  to  idiosyncrasies,  compared  to  the  mil- 
lions of  doses  which  have  been  ingested  appears 
singularly  small. 

Acute  poisoning  in  children  is  manifested  by 
vomiting,  abdominal  pain,  diarrhea,  cyanosis, 
fatigue,  vertigo,  somnolence,  palpitation,  muscu- 
lar spasms,  delirium  and  coma.  Urticaria  is  seen. 


Treatment  consists  of  gastric  lavage,  cathartics, 
an  enema,  oxygen  inhalation  and  nikethamide, 
pentylenetetrazole,  etc.  Venesection  and  replace- 
ment of  blood  capable  of  carrying  oxygen  may  be 
necessary. 

It  seems  definitely  established  that  the  con- 
tinued use  of  acetanilid  in  large  doses  (1.5  Gm. 
daily)  leads  to  anemia  and  degenerative  changes 
in  the  heart  and  other  organs.  Chronic  poisoning 
is  manifested  by  cyanosis,  anorexia,  cachexia, 
anemia,  varied  psychic  and  neurologic  disorders, 
lassitude,  insomnia  and  headache  (Lundsteen, 
Meulengracht  and  Rischel,  Acta  med.  Scandinav., 
1938,  96,  462).  Since  headache  may  be  the 
symptom  for  which  the  drug  was  taken,  a  vicious 
cycle  is  established.  Splenomegaly  is  often  asso- 
ciated with  the  hemolytic  anemia.  Tolerance  to 
large  doses  may  develop  and  withdrawal  symp- 
toms, such  as  acute  mania,  have  been  reported 
(Austin,  J.A.M.A.,  1942,  120,  911;  Mcintosh, 
N.  Carolina  M.  J.,  1940,  1,  143;  Payne,  /. 
Pharmacol,  1935,  53,  401). 

The  repeated  use  of  acetanilid  in  large  doses 
leads  to  a  change  in  the  color  of  the  blood. 
Although  Young  and  Wilson  (/.  Pharmacol,  1926, 
27,  1334)  believed  that  the  new  pigment  is  due  to 
decomposition  products  of  />ara-aminophenol,  the 
observations  of  Harrop  and  Waterfield  (J. A.M. A., 
1930,  95,  647),  of  Smith  (/.  Pharmacol,  1940, 
70,  171)  and  many  others  seem  to  leave  no  room 
for  doubt  that  there  is  a  formation  of  either 
methemoglobin,  sulfhemoglobin,  or  both.  Bran- 
denburg and  Smith  (Am.  Heart  J.,  1951,  42,  582) 
reported  62  clinical  cases  of  sulfhemoglobinemia, 
44  of  which  followed  the  prolonged  ingestion  of 
acetanilid  alone  or  in  combination  with  potassium 
bromide  and  caffeine.  Reynolds  and.  Ware 
(J.A.M.A.,  1952,  149,  1538),  in  reporting  6  cases 
of  sulfhemoglobinemia  following  the  prolonged 
use  of  acetanilid,  emphasize  that  this  pigment 
occurs  more  commonly  than  methemoglobin.  Ac- 
companying the  change  in  hemoglobin  there  is  a 
diminution  in  the  oxygen-carrying  power  of  the 
blood.  Methemoglobin  is  rapidly  reversed  to 
normal  hemoglobin  by  the  enzyme  systems  in  the 
red  blood  cells  as  soon  as  the  offending  agent  is 
removed,  but  sulfhemoglobin  is  not  reversible  to 
hemoglobin  and,  once  formed,  it  persists  for  the 
life  of  the  red  cell.  The  two  pigments  may  be 
differentiated  by  spectroscopic  examination  of 
the  blood. 

Whether  acetanilid  is  to  be  classed  as  a  habit- 
forming  drug  depends  largely  on  what  one  means 
by  the  term  "habit-forming"  (whether  psychic  or 
physical  dependence).  Undoubtedly,  there  are 
hundreds  of  persons  who  use  acetanilid  daily, 
just  as  there  are  millions  who  are  addicted  to  caf- 
feine beverages,  but  we  do  not  believe  it  is  justi- 
fiable to  speak  of  it  as  a  habit-forming  drug  in  the 
sense  that  opium  or  alcohol  is.  despite  the  report 
of  Stewart  (J. A.M. A.,  1905.  44,  1724).  Just  how 
much  of  the  drug  is  needed  to  bring  about  these 
noxious  effects  it  is  impossible  to  say.  Acetanilid 
is  relatively  safe  as  a  therapeutic  agent  but  its 
habitual  use  by  the  laity  is  not  to  be  encouraged 
(see  also  Hanzlik,  /.  Am.  Dent.  A.,  Sept.,  Oct. 
and  Nov.,  1940). 

Dose. — The  usual  dose  of  acetanilid  is  200  mg. 


Part  I 


Acetarsone 


(approximately  3  grains),  with  a  range  of  200  to 
500  mg. ;  not  more  than  1  Gm.  should  be  taken  in 
24  hours. 

Storage. — Preserve  "in  well-closed  con- 
tainers." N.F. 

ACETANILID  TABLETS.     N.F. 

[Tabellae  Acetanilidi] 

"Acetanilid  Tablets  contain  not  less  than  94 
per  cent  and  not  more  than  106  per  cent  of  the 
labeled  amount  of  CsHgNO."  N.F. 

Assay. — A  representative  sample  of  tablets, 
equivalent  to  about  300  mg.  of  acetanilid,  is 
digested  with  petroleum  benzin  to  remove  lubri- 
cants, after  which  the  acetanilid  is  extracted  with 
chloroform,  the  solvent  evaporated,  and  the  resi- 
due of  acetanilid  dried  at  about  80°  for  2  hours, 
and  finally  weighed  as  CsHgNO.  N.F. 

Storage. — Preserve  "in  well-closed  con- 
tainers." N.F. 

Usual  Sizes. — 3  and  5  grains  (approximately 
200  and  300  mg.). 

ACETARSONE.  N.F.  (B.P.)  LP. 

3-Acetamido-4-hydroxybenzenearsonic 
Acid,   [Acetarsonum] 


As0(0H)o 


NHC0CH-, 


"Acetarsone,  dried  at  105°  for  1  hour,  yields 
not  less  than  98.8  per  cent  and  not  more  than 
101.4  per  cent  of  CsHioAsNOs."  N.F.  The  B.P. 
defines  acetarsol  as  3-acetamido-4-hydroxyphenyl- 
arsonic  acid,  and  requires  it  to  contain  not  less 
than  27.1  per  cent  and  not  more  than  2  7.5  per 
cent  of  As,  calculated  with  reference  to  the  sub- 
stance dried  to  constant  weight  at  105°.  The  LP. 
limits  are  26.8  to  27.5  per  cent  of  As,  with  refer- 
ence to  the  substance  dried  at  100°  for  4  hours. 

B.P.  Acetarsol.  I. P.  Acetarsolum.  N-acetyl-4-hydroxy-m- 
arsanilic  acid.  Stovarsol  (Merck),  Kharophen,  Orarsan, 
Spirocid. 

The  intermediate  from  which  acetarsone,  as 
well  as  arsphenamine  and  most  other  arsenicals, 
may  be  prepared  is  3-nitro-4-hydroxyphenyl- 
arsonic  acid  (for  method  of  obtaining  it  see  under 
Arsphenamine) .  By  reducing  only  the  nitro  group 
— not  the  arsenic — in  this  intermediate  and 
acetylating  the  resulting  amino  group  acetarsone 
is  produced. 

Description. — "Acetarsone  occurs  as  a  white 
or  slightly  yellow,  odorless  powder.  It  is  stable  at 
ordinary  temperatures.  Acetarsone  dissolves  in 
solutions  of  alkali  hydroxides  or  carbonates.  It  is 
slightly  soluble  in  water  and  insoluble  in  alcohol. 
Its  saturated  aqueous  solution  is  acid  to  litmus 
paper."  N.F.  The  B.P.  gives  the  melting  point  as 
about  240°,  with  decomposition. 

Standards  and  Tests. — Identification. — (1) 
A  yellow  precipitate  is  produced  on  adding  2  Gm. 
of  sodium  hydrosulfite  to  a  solution  of  1  Gm.  of 
acetarsone  in   10  ml.  of  sodium  hydroxide  T.S. 


diluted  with  10  ml.  of  water,  the  mixture  being 
heated  in  a  water  bath  for  20  minutes;  after  de- 
canting the  supernatant  liquid  the  precipitate  dis- 
solves in  an  excess  of  sodium  hydroxide  T.S.  (2) 
A  yellow  precipitate,  soluble  in  ammonium  carbo- 
nate T.S.,  is  produced  when  hydrogen  sulfide  is 
passed  into  the  solution  resulting  from  the  assay 
for  arsenic.  (3)  A  solution  of  100  mg.  of  acetar- 
sone in  5  ml.  of  sodium  hydroxide  T.S.  is  evapo- 
rated to  about  3  ml.,  cooled,  2  or  3  drops  of 
alcohol  and  2  ml.  of  sulfuric  acid  added  and  the 
mixture  heated  gently :  an  odor  of  ethyl  acetate  is 
apparent.  Loss  on  drying. — Not  over  2  per  cent, 
when  dried  at  105°  for  1  hour.  Residue  on  igni- 
tion.— Not  over  0.2  per  cent.  Solubility  in  sodium 
carbonate. — A  practically  clear  solution,  not 
darker  than  a  pale  yellow,  is  obtained  from  1  Gm. 
of  acetarsone  and  10  ml.  of  sodium  carbonate 
T.S.  Aminohydroxyphenylarsonic  acid. — No  red 
or  brown  color  is  produced  on  adding  2  drops  of  a 
1  in  30  potassium  dichromate  solution  to  the  fil- 
trate obtained  by  shaking  1  Gm.  of  acetarsone 
with  10  ml.  of  a  mixture  of  equal  volumes  of  di- 
luted hydrochloric  acid  and  water  and  then  filter- 
ing. Inorganic  arsenates. — No  precipitate  is  pro- 
duced on  adding  a  slight  excess  of  ammonia  T.S. 
and  2  ml.  of  magnesia  mixture  T.S.  to  a  solution 
of  500  mg.  of  acetarsone  in  10  ml.  of  water;  on 
heating  the  solution  for  10  or  15  minutes  a  pre- 
cipitate will  form.  N.F. 

As  the  test  for  aminohydroxyphenylarsonic 
acid  the  B.P.  specifies  that  the  color  produced 
when  a  solution  of  unhydrolyzed  acetarsone  is 
diazotized  and  coupled  with  betanaphthol  shall 
not  be  deeper  than  that  obtained  when  about 
%ooth  of  the  amount  of  acetarsone  is  hydrolyzed 
by  acid  and  similarly  diazotized  and  coupled. 
Loss  on  drying  to  constant  weight  at  105°  is 
limited  to  0.5  per  cent.  A  limit  test  for  chloride 
is  also  provided  by  the  B.P. 

Assay. — In  the  N.F.  assay  about  200  mg.  of 
dried  acetarsone  is  decomposed  with  potassium 
permanganate  and  sulfuric  acid.  Hydrogen  per- 
oxide is  added  to  reduce  the  excess  permanganate 
and  the  pentavalent  arsenic  is  reduced  to  the 
trivalent  state  by  iodide;  the  liberated  iodine  is 
titrated  with  0.1  iV  sodium  thiosulfate.  Each  ml. 
of  0.1  N  sodium  thiosulfate  represents  13.75  mg. 
of  CsHioAsNOs.  The  B.P.  assay  provides  for 
oxidation  of  the  acetarsone  with  fuming  nitric 
acid  and  sulfuric  acid.  The  nitric  acid  is  subse- 
quently decomposed  with  the  aid  of  ammonium 
sulfate,  the  arsenic  reduced  by  iodide  and,  finally, 
in  the  presence  of  sodium  bicarbonate,  the  tri- 
valent arsenic  is  oxidized  to  the  pentavalent  state 
by  titration  with  0.1  iV  iodine.  The  LP.  assay  is 
practically  the  same  as  that  of  the  B.P. 

Uses. — This  pentavalent  arsenical  was  among 
those  which  Ehrlich  tested  but  rejected  because 
it  produced  severe  nerve  disorders  in  mice.  In 
1921  Fourneau  introduced  it  as  a  preventive  and 
curative  remedy  for  syphilis.  Its  value  in  this 
condition  was  studied  by  Raiziss  {Arch.  Dermat. 
Syph.,  1935,  25,  799)  who  found  that  it  appar- 
ently penetrates  into  the  spinal  canal  more  easily 
than  trivalent  arsenicals.  While  it  is  apparently 
less  efficient  than  arsphenamine  as  an  antisyphi- 
litic,  it  is  effective  when  given  by  mouth.  How- 


8 


Acetarsone 


Pari   I 


ever,  doses  which  are  effective  for  adult  syphilis 
produce  toxic  effects  in  from  7  to  20  per  cent  of 
patients.  Because  of  its  toxicity  it  is  generally  not 
recommended  for  the  treatment  of  congenital  lues 
in  infants  (Vem.  Dis.  Inform.,  1942,  Suppl.  18, 
1-92).  Considering  the  availability  of  other  and 
safer  methods  of  treating  syphilis  the  risk  of 
toxicity  from  such  use  of  acetarsone  is  not  justi- 
fied. Both  acetarsone  and  its  bismuth  salt  have 
been  employed  as  an  adjuvant  to  the  malarial 
therapy  of  neurosvphilitic  insanitv  (Parkenham- 
Walsh.  J.  Meat.  Sc,  1942.  88,  344). 

Yaws  has  been  successfully  and  cheaply  treated 
with  oral  doses  of  250  mg.  daily  in  3  courses  of 
20  days  each,  separated  by  14-day  intervals  with- 
out medication  (Pardo-Costello,  Arch.  Dermat. 
Syph.,  1939.  40,  762). 

Vincent's  angina  responds  favorably  to  250  mg. 
of  acetarsone  in  a  paste  made  with  glycerin  or 
water  and  locally  applied  (Maxwell.  Pract.,  1936. 
2,  660).  In  a  jelly  vehicle  it  has  given  prompt 
relief  in  fusospirochetal  balanitis  (Thompson. 
Brit.  M.  J.,  1943.  2,  485).  Meigs  (New  Eng.  J. 
Med.,  1942.  226,  562)  and  others  have  used 
acetarsone  with  success  in  trichomonas  vaginitis; 
100  mg.  may  be  applied  as  a  powder  or  in  aqueous 
solution  in  the  office,  and  a  tablet  or  impregnated 
tampon  containing  acetarsone,  with  glucose,  lactic 
and  boric  acids,  starch,  sodium  bicarbonate  and 
tartaric  acid  prescribed  for  insertion  at  bedtime. 
A  powder  containing  12.5  per  cent  of  acetarsone 
with  kaolin  and  sodium  bicarbonate  is  used  by 
some  physicians  for  insufflation  every  second  or 
third  day  until  three  or  four  treatments  have  been 
given. 

In  amebic  dysentery  Faust.  D'Antoni  and 
Sawitz  {Clin.  Med.,  1943.  50,  261)  found  acet- 
arsone highly  effective;  they  administered  260 
mg.  twice  a  day  for  two  days,  then  three  times 
daily  for  three  days.  Balantidiasis  also  responds 
to  this  drug  (McCarey.  Brit.  M.  J.,  1952,  1,  629). 
Acetarsone  is  reported  to  be  valuable  in  the 
treatment  of  pemphigus  (Oppenheim  and  Cohen, 
Arch.  Dermat.  Syph.,  1950.  61,  500);  and  of 
diphtheria  carriers,  being  administered  by  nasal 
instillation  (Brit.  M.  J.,  1937.  1,  2). 

Acetarsone  is  completely  absorbed,  after  oral 
administration,  and  rapidly  excreted  in  the  urine, 
with  only  small  amounts  stored  in  the  fiver  and 
other  tissues  (Dimter  and  Allin.  Ztschr.  Ki?idcrh., 
1943.  63,  760).  It  should  be  remembered  that 
although  acetarsone  is  generally  given  by  mouth 
it  is  capable  of  giving  rise  to  the  same  group  of 
toxic  manifestations  that  follow  arsphenamine. 
The  effective  dose  nearly  equals  the  toxic  dose. 
Toxic  effects  are  infrequent  if  rest  periods  of 
three  to  five  days  are  prescribed  between  each 
three  to  five  days  of  administration.  Deaths  have 
been  due  to  nephritis,  neuritis,  encephalitis,  ex- 
foliative and  bullous  dermatitis,  hepatitis,  aplastic 
anemia  and  indefinite  causes.  Less  severe  reac- 
tions include  erythema,  diarrhea,  vomiting,  fever, 
albuminuria,  paresthesias  and  vertigo.  Acetarsone 
is  contraindicated  in  patients  with  disease  of  the 
cardiovascular  system,  impaired  liver  or  kidney 
function,  optic  neuritis,  fever  or  recent  hemor- 
rhage (Ven.  Dis.  Inform.,  1942,  Suppl.  18, 1-92).  ® 


Dose. — The  range  is  from  60  to  250  mg.  (ap- 
proximately 1  to  4  grains),  two  or  three  times  a 
day.  It  should  not  be  continued  for  more  than  a 
week  or  10  days;  treatment  may  be  resumed  after 
a  rest  period. 

Derivatives. — A  water-soluble  sodium  deriva- 
tive of  acetarsone.  suitable  for  the  preparation  of 
injections,  is  sold  abroad.  Other  derivatives  are 
the  bismuth  compound,  generally  injected  as  an 
oil  suspension,  and  the  water-soluble  diethyla- 
mine  acetarsol,  known  as  Acetylarsan  (Merck), 
used  intramuscularly  or  subcutaneously. 

Storage. — Preserve    "in    well-closed    contain- 


ers." X.F. 


ACETARSONE  TABLETS. 

[Tabellae  Acetarsoni] 


X.F. 


'Acetarsone  Tablets  contain  not  less  than  92.5 
per  cent  and  not  more  than  107.5  per  cent  of  the 
labeled  amount  of  CvHu.AsXO-,."  X.F. 

Usual  Sizes.— 10,  50,  100,  and  250  mg.  (ap- 
proximately %,  H,  1%,  and  4  grains). 

ACETIC  ACID.     U.S.P.,  B.P. 

[Acidum  Aceticum] 

"Acetic  Acid  is  a  solution  containing  not  less 
than  36  per  cent  and  not  more  than  37  per  cent, 
by  weight,  of  C2H4O2."  U.S.P.  The  B.P.  requires 
33.0  per  cent  w/w  of  C2H4O2   (limits,  32.5   to 

OO.J). 

Ethanoic  Acid.  Acetum  Concentratum :  Acidum  Aceticum 
Dilutum  (.Get.,  Sp.)  Ger.  Verdiinnte  Essigsaure.  Sp.  Acido 
acetico  diluido. 

Formerly  the  chief  commercial  source  of  acetic 
acid  was  the  destructive  distillation  of  wood. 
When  carbonized  out  of  contact  with  air.  wood 
yields  many  volatile  products,  among  which  are 
an  acid  liquor  called  pyroligneons  acid,  an  empy- 
reumatic  oil.  and  tar  containing  creosote  and  some 
other  proximate  principles  (see  Pine  Tar).  When 
the  carbonization  is  performed  in  closed  vessels. 
these  products  may  be  collected,  and,  at  the  same 
time,  a  large  amount  of  charcoal  be  obtained.  In 
the  case  of  resinous  woods,  wood  oil  and  turpen- 
tine oil  are  obtained  before  the  charring  tempera- 
ture is  reached. 

Crude  pyroligneous  acid,  sometimes  called 
pyroligneons  vinegar,  or  wood  vinegar,  is  a  dark 
brown  liquid,  having  a  strong  smoky  odor,  and 
consisting  of  acetic  acid,  methanol,  acetone,  water 
and  more  or  less  tar.  At  one  time  the  crude 
pyroligneous  acid  was  converted  to  calcium  ace- 
tate by  treatment  with  lime,  and  the  acetic  acid 
obtained  by  subsequent  distillation  with  sulfuric 
acid.  This  method  of  recovering  acetic  acid  from 
pyroligneous  acid  is  no  longer  economically  prac- 
ticable; at  present,  the  acetic  acid  is  separated 
by  processes  invoking  solvent  extraction,  as  with 
isopropyl  ether,  and  removal  of  water  by  azeo- 
tropic  distillation,  using  a  water-entraining  liquid 
(see  Glacial  Acetic  Acid).  The  product  can  readily 
be  concentrated,  if  desired,  to  contain  over  99  per 
cent  of  CH3COOH. 

During  the  first  World  War  the  facilities  of 
the  wood  distillation  industry  were  found  to  be 


Part  I 


Acetic   Acid 


entirely  inadequate  to  supply  the  demand  for 
acetic  acid  and  it  was  made  from  molasses  which 
had  been  fermented  into  alcohol.  In  this  process 
conversion  of  the  molasses  alcohol  into  acetic  acid 
was  accomplished  by  the  quick  fermentation  proc- 
ess in  which  weak  alcohol  was  passed  through 
percolators  filled  with  beech  wood  shavings  which 
had  been  inoculated  with  Mycoderma  aceti.  An- 
other method  for  the  rapid  production  of  acetic 
acid,  introduced  during  the  same  war,  depends  on 
the  conversion  of  acetylene  to  acetaldehyde  which 
is  then  readily  oxidized  to  acetic  acid  by  means 
of  air;  catalysts  are  employed  in  both  reactions. 

Still  another  process  for  the  manufacture  of 
acetic  acid  is  the  oxidation  of  alcohol  vapor  by 
air  in  the  presence  of  suitable  catalysts.  Acetic 
acid  may  also  be  produced  by  heating  a  mixture 
of  carbon  monoxide  and  methyl  alcohol  in  the 
presence  of  catalysts. 

Description. — "Acetic  Acid  is  a  clear,  color- 
less liquid,  having  a  strong,  characteristic  odor, 
and  a  sharply  acid  taste.  Acetic  Acid  is  miscible 
with  water,  with  alcohol,  and  with  glycerin.  The 
specific  gravity  of  acetic  acid  is  about  1.045." 
U.S.P. 

The  specific  gravity  of  acetic  acid  increases 
with  concentration  to  a  maximum  of  1.0681  at 
25°  C.  (76-79  per  cent  HC2H3O2),  after  which  it 
decreases  until  it  reaches  1.0471  at  25°  C,  the 
specific  gravity  of  the  100  per  cent  acid.  The 
specific  gravities  of  the  glacial  (100  per  cent)  and 
the  39  per  cent  acid  are  practically  the  same,  and 
this  applies  also  to  the  74  and  81  per  cent  acids. 

Standards  and  Tests. — Identification. — 
Acetic  acid  responds  to  tests  for  acetate.  Non- 
volatile residue. — Not  over  1  mg.  of  residue  re- 
mains when  20  ml.  of  acetic  acid  is  evaporated  on 
a  water  bath  and  dried  at  105°  for  1  hour. 
Chloride. — No  opalescence  is  produced  when  silver 
nitrate  T.S.  is  added  to  a  1  in  10  aqueous  solution 
of  acetic  acid.  Sulfate. — No  turbidity  is  produced 
when  barium  chloride  T.S.  is  added  to  a  1  in  10 
aqueous  solution  of  acetic  acid.  Heavy  metals. — 
The  limit  is  10  parts  per  million.  Readily  oxidiz- 
able  substances. — The  color  of  4  ml.  of  acetic 
acid,  20  ml.  of  distilled  water,  and  0.3  ml.  of 
0.1  N  potassium  permanganate  does  not  change 
to  brown  at  once  nor  does  it  lose  its  pink  tint  en- 
tirely in  less  than  30  seconds.  U.S.P. 

The  B.P.  specifies  a  test  for  limit  of  formic 
acid  and  of  oxidizable  impurities  in  which  the 
acid  is  mixed  with  0.1  N  potassium  dichromate 
and  sulfuric  acid  and,  after  standing  for  a  minute, 
with  a  solution  of  potassium  iodide;  a  yellow  or 
brown  color  should  be  produced  immediately,  in- 
dicating the  presence  of  less  than  the  limit  of 
impurity.  An  arsenic  limit  of  2  parts  per  million 
and  a  lead  limit  of  1  part  per  million  are  stipu- 
lated. Other  tests  are  similar  to  corresponding 
tests  in  the  U.S.P. 

Assay. — A  sample  of  about  6  ml.  is  weighed, 
diluted  with  water,  and  titrated  with  1  N  sodium 
hydroxide,  using  phenolphthalein  indicator.  Each 
ml.  of  I  N  sodium  hydroxide  represents  60.05  mg. 
of  C2H4O2.  U.S.P. 

Uses. — Acetic  acid  has  an  active  astringent  ac- 
tion and  is  occasionally  used  for  this  purpose  in 


skin  diseases;  it  is  also  employed  as  a  styptic. 
Along  with  copious  amounts  of  water,  a  3  per 
cent  or  less  concentrated  solution  of  acetic  acid 
may  be  used  to  neutralize  alkali  burns  of  the  skin; 
the  heat  produced  in  the  neutralization  of  residual 
alkali  may  aggravate  the  injury  if  the  acid  is  con- 
centrated. A  0.5  per  cent  solution  is  used  as  a 
cleansing  agent  or  for  moistening  compresses  on 
infected  burns  or  other  wounds  of  the  skin;  this 
concentration  is  bacteriostatic  for  most  common 
bacteria.  Nielson  (J. A.M. A.,  1934,  102,  1179) 
recommended  18  per  cent  acetic  acid  as  a  local 
application,  every  third  or  fourth  day,  in  the 
treatment  of  various  forms  of  ringworm  of  the 
skin,  such  as  tinea  capitis  and  athlete's  foot.  A 
1  per  cent  solution  is  an  effective  surgical  dress- 
ing for  pyocyaneus  infections.  Boiled  household 
vinegar,  equivalent  to  5  per  cent  acetic  acid,  was 
instilled  into  the  external  auditory  canal  in  cases 
with  purulent  drainage  from  chronic  otitis  media 
by  Ochs  (Arch.  Otolaryng.,  1950,  52,  935);  when 
the  canal  was  thoroughly  cleansed,  a  tampon  of 
cotton  was  inserted  against  the  drum,  moistened 
with  the  vinegar  and  left  for  2  days.  Infection 
cleared  after  1  to  3  treatments  in  36  ears  and 
relapsed  in  only  5.  In  chronic  pulmonary  suppura- 
tion due  in  part  at  least  to  Pseudomonas  aeru- 
ginosa, Currence  (Am.  J.  Dis.  Child.,  1952,  83, 
637)  used  1  ml.  of  a  1 :  1000  solution  as  an  aerosol 
three  times  daily;  symptoms  were  relieved  al- 
though the  bacteria  persisted.  Steam  inhalations 
from  30  ml.  of  vinegar  in  a  liter  of  water  were 
also  used.  For  urinary  infections  with  cystitis  an 
0.5  to  1  per  cent  solution  is  used  as  a  bladder 
irrigation,  especially  for  ammonia-forming  bac- 
teria. As  an  acid  (pH  5)  vaginal  douche,  1  to  2 
per  cent  acetic  acid  (%.  to  x/z  cup  of  white  vine- 
gar to  2  quarts  of  warm  water)  is  commonly 
used  (Hirst,  Am.  J.  Obst.  Gynec,  1952,  64),  in 
the  treatment  of  Trichomonas  vaginalis  and  other 
types  of  vaginitis.  For  contraceptic  purposes,  1 
per  cent  acetic  acid  has  been  incorporated  in  a 
mucilaginous  vehicle  containing  tragacanth,  acacia, 
agar,  etc. 

Internally,  acetic  acid  is  occasionally  employed 
as  a  refrigerant  drink,  but  it  is  less  palatable  than 
citric  acid  solution.  Because  it  is  completely 
oxidized  in  the  body  acetic  acid  does  not  affect 
the  acidity  of  the  general  system.  As  an  emer- 
gency remedy  in  hemorrhage  from  the  stomach, 
diluted  acetic  acid,  mixed  with  an  equal  volume 
of  water — so  that  the  solution  contains  about 
3  per  cent  of  HC2H3O2 — has  been  used  in  table- 
spoonful  doses  every  few  minutes  as  required.  Be- 
cause of  its  volatility  and  pungency,  the  vapor  of 
acetic  acid  is  used  for  inhalation  in  the  treatment 
of  faintness  and  sick  headache,  in  the  same  man- 
ner as  smelling  salts.  This  action,  like  that  of 
ammonia,  is  due  to  reflexes  from  irritation  of  the 
mucous  membrane  of  the  nose.  The  N.F.V.  recog- 
nized, under  the  name  Acetum  Aromaticum,  a 
mixture  containing  several  volatile  oils,  with 
acetic  acid,  for  this  particular  use. 

Acetic  acid  possesses  extraordinary  solvent 
power  for  many  organic  substances,  and  enhances 
the  miscibility  of  many,  otherwise  immiscible, 
liquids  with  water.  Charles  F.  Squibb  and  J.  P. 


10 


Acetic   Acid 


Part   I 


Remington  called  attention  to  the  solubilizing 
effect  of  acetic  acid  when  used  in  the  menstrua 
for  extracting  certain  drugs,  and  proposed  a  class 
of  preparations,  called  acetracts,  as  substitutes  for 
the  conventionally  prepared  solid  extracts.  |v] 

Dose,  0.3  to  0.6  ml.  (approximately  5  to  10 
minims),  diluted  with  water;  topically,  0.5  to  20 
per  cent  solutions  are  used. 

Storage. — Preserve  "in  tight  containers." 
U.S.P. 

Off.  Prep.— Diluted  Acetic  Acid,  N.F.,  B.P.; 
Aluminum  Subacetate  Solution,  U.S. P.;  Lobelia 
Tincture,  N.F. 

GLACIAL  ACETIC  ACID.    U.S.P.,  B.P. 

[Acidum  Aceticum  Glaciate] 
CH3.COOH 

"Glacial  Acetic  Acid  contains  not  less  than  99.4 
per  cent,  by  weight,  of  C2H4O2."  U.S.P.  The  B.P. 
rubric  is  not  less  than  99.0  per  cent  C2EUO2. 

Crystallizable  Acetic  Acid.  Acidum  Aceticum  Concen- 
tratum;  Acidum  Aceticum  {Fr.,  Ger.,  It.,  Sp.).  Fr.  Acide 
acetique;  Acide  acetique  cristallisable;  Acide  acetique  pur. 
Ger.  Essigsaure;  Eisessig.  It.  Acido  acetico.  Sp.  Acido 
acetico;  Acido  Acetico  Glacial;  Acido  etanoico. 

Formerly  glacial  acetic  acid  was  prepared  by 
distilling  a  mixture  of  anhydrous  sodium  acetate 
and  sulfuric  acid,  but  it  is  now  prepared  by  con- 
centrating weaker  solutions  of  acetic  acid.  Com- 
mercial processes  depend  upon  the  separation  of 
water  by  fractional  distillation,  by  formation  of 
compounds  with  anhydrous  salts,  by  refrigeration, 
by  entrainment  with  an  organic  solvent  or  by 
other  chemical  reactions.  Thus,  acetic  acid  may 
be  rendered  anhydrous  by  rectification  with  dieth- 
ylcarbonate  which  lowers  the  boiling  point  of 
the  water.  By  this  means  50  per  cent  acetic  acid 
may  be  distilled  to  produce  an  acetic  acid  of  99.8 
to  100  per  cent  purity.  In  another  process  acetic 
acid  is  dehydrated  by  treating  it  with  a  water- 
entraining  liquid  such  as  ethylene  or  propylene 
chloride  which,  together  with  the  entrained  water, 
is  subsequently  separated  from  the  acetic  acid  by 
distillation. 

Description. — "Glacial  Acetic  Acid  is  a  color- 
less, clear  liquid,  having  a  pungent,  characteristic 
odor,  and,  when  well  diluted  with  water,  an  acid 
taste.  It  boils  at  about  118°  and  has  a  specific 
gravity  of  about  1.049.  Glacial  Acetic  Acid  is 
miscible  with  water,  with  alcohol,  and  with  glyc- 
erin. Glacial  Acetic  Acid  congeals  at  a  tempera- 
ture not  lower  than  15.6°."  U.S.P.  The  B.P.  states 
that  glacial  acetic  acid  crystallizes  at  about  10° 
and  does  not  completely  remelt  until  warmed  to 
about  15°.  The  freezing  point  is  given  as  not  lower 
than  14.8°. 

Standards  and  Tests. — Identification. — Tests 
for  acetate  are  given  by  a  mixture  of  1  volume  of 
glacial  acetic  acid  and  2  volumes  of  water.  Non- 
volatile residue. — Not  over  1  mg.  of  residue  re- 
mains when  20  ml.  of  glacial  acetic  acid  is  evapo- 
rated in  a  tared  porcelain  dish  and  dried  at  105° 
for  1  hour.  Chloride. — Silver  nitrate  T.S.  pro- 
duces no  opalescence  when  added  to  a  1  in  20 
aqueous  solution  of  glacial  acetic  acid.  Sulfate. — 
Barium  chloride  T.S.  produces  no  turbidity  when 


added  to  a  1  in  10  aqueous  solution  of  glacial 
acetic  acid.  Heavy  metals. — The  limit  is  10  parts 
per  million.  Readily  oxidizable  substances. — The 
pink  color  of  a  mixture  of  2  ml.  of  glacial  acetic 
acid,  10  ml.  of  water,  and  0.1  ml.  of  0.1  N  potas- 
sium permanganate  is  not  changed  to  brown  within 
2  hours.  U.S.P. 

The  tests  described  in  the  B.P.  are  similar  to 
those  described  under  Acetic  Acid,  exceptions 
being  the  arsenic  limit  of  6  parts  per  million  and 
the  lead  limit  of  3  parts  per  million. 

Assay. — A  sample  of  about  2  ml.  of  acid  is 
weighed  in  a  glass-stoppered  flask,  diluted  with 
distilled  water,  and  titrated  with  1  N  sodium  hy- 
droxide, using  phenolphthalein  T.S.  as  indicator. 
Each  ml.  of  1  N  sodium  hydroxide  is  equivalent 
to  60.05  mg.  of  C2H4O2.  U.S.P. 

Uses. — Glacial  acetic  acid  is  comparatively 
little  employed  as  a  therapeutic  agent;  it  is  official 
chiefly  because  it  is  an  ingredient  of  other  official 
preparations.  It  was  formerly  used  to  some  extent 
as  a  caustic  for  the  removal  of  warts  and  corns, 
but  has  been  largely  replaced  by  the  more  efficient 
trichloroacetic  acid  or  the  high-frequency  electric 
current.  When  properly  diluted,  it  may,  of  course, 
be  employed  for  the  various  purposes  described 
under  Acetic  Acid,  (v] 

Glacial  acetic  acid  possesses  the  property  of 
dissolving  a  number  of  substances,  such  as  volatile 
and  fixed  oils,  camphor,  resins,  gelatin,  etc.  It 
also  promotes  the  mutual  solubility  of  partially 
miscible  liquids.  As  it  attracts  moisture  from  the 
atmosphere,  it  should  be  preserved  in  well-stop- 
pered bottles. 

Toxicology. — The  ingestion  of  glacial  acetic 
acid  is  followed  by  severe  pain  in  the  mouth, 
throat  and  abdomen.  White  plaques  and  ulcers 
are  seen  on  the  mucous  membranes.  Vomiting  and 
hematemesis  occur  and  diarrhea  may  follow. 
Hoarseness,  rapid  and  shallow  respiration,  and 
circulatory  collapse  appear.  Body  temperature  is 
subnormal.  Albuminuria,  oliguria  and  uremia  may 
develop. 

Morphine  injection  is  indicated  for  pain.  Gas- 
tric lavage  or  bicarbonate  salts  are  contraindicated 
since  they  may  rupture  the  eroded  stomach.  A 
suspension  of  60  Gm.  of  calcium  or  magnesium 
hydroxide  in  500  ml.  of  water  should  be  ingested 
if  possible.  Milk,  egg  white  and  other  demulcent 
substances  are  indicated.  Parenteral  fluids  and 
supportive  measures  are  important. 

Chronic  poisoning  causes  pallor,  cachexia,  ero- 
sion of  the  teeth,  halitosis,  bronchitis  and  gastro- 
intestinal disturbances.  Industrial  exposure  to  the 
vapors  results  in  conjunctivitis  and  blepharitis. 

Storage. — Preserve  "in  tight  containers." 
U.S.P. 

Off.  Prep. — Aluminum  Acetate  Solution, 
U.S. P.;  Cantharides  Tincture,  N.F.;  Strong  Solu- 
tion of  Ammonium  Acetate,  B.P. 


DILUTED   ACETIC   ACID.    N.F.    (B.P.) 

[Acidum  Aceticum  Dilutum] 

"Diluted  Acetic  Acid  is  a  solution  containing, 
in  each  100  ml.,  not  less  than  5.7  Gm.  and  not 
more  than  6.3  Gm.  of  C2H4O2."  N.F. 


Part  I 


Acetone 


11 


Diluted  acetic  acid  may  be  prepared  by  mixing 
158  ml.  of  acetic  acid  with  sufficient  purified 
water  to  make  1000  ml.  N.F. 

The  B.P.  formula  yields  a  preparation  of  the 
same  strength. 

B.P.  Dilute  Acetic  Acid.  Fr.  Acide  acetique  dilue ; 
Solution  aqueuse,  au  dixieme,  d'acide  acetique. 

Description. — "Diluted  Acetic  Acid  is  a  clear, 
colorless  liquid  having  a  characteristic  odor,  and 
a  sharply  acid  taste.  Diluted  Acetic  Acid  is 
miscible  with  water,  with  alcohol  and  with  glyc- 
erin. Its  specific  gravity  is  about  1.008."  N.F. 

For  therapeutic  uses  of  this  substance,  see  under 
Acetic  Acid. 

Storage. — Preserve  "in  tight  containers."  N.F. 

Off.  Prep. — Ammonium  Acetate  Solution; 
Iron  and  Ammonium  Acetate  Solution;  Squill 
Vinegar,  N.F.;  Tincture  of  Ipecac,  B.P. 


ACETOMENAPHTHONE. 

Acetomenaphthonum 


B.P. 


The  B.P.  defines  Acetomenaphthone  as  1 :4- 
diacetoxy-2-methylnaphthalene  and  requires  not 
less  than  98.0  per  cent  of  C15H14O4,  referred  to 
the  substance  dried  to  constant  weight  at  80°. 

Menadiol  Diacetate.  2-Methyl-l,4-naphthohydroquinone 
Diacetate. 

The  B.P.  states  that  acetomenaphthone  may  be 
prepared  by  reducing  2-methyl-l,4-naphthoquinone 
(menadione)  with  zinc  and  acetic  acid  in  the  pres- 
ence of  acetic  anhydride.  The  compound  thus 
represents  menadione  which  has  been  reduced  to 
its  corresponding  hydroquinone  and  the  two 
hydroxyl  groups  of  the  latter  acetylated.  In  the 
B.P.  synthesis  nascent  hydrogen  produced  by  the 
interaction  of  zinc  and  acetic  acid  effects  the  re- 
duction, while  the  acetic  anhydride  accomplishes 
the  acetylation.  The  synthesis  of  acetomenaph- 
thone has  also  been  described  by  Anderson  and 
Newman  (/.  Biol.  Chem.,  1933,  103,  405),  who 
prepared  it  as  an  intermediate  in  the  synthesis  of 
the  tubercle  bacillus  pigment  phthiocol,  which  is 
2-methyl-3-hydroxy- 1 ,4-naphthoquinone. 

Description  and  Standards. — Acetomenaph- 
thone is  a  white,  crystalline  powder,  odorless  or 
with  a  slight  odor  of  acetic  acid.  It  is  almost  in- 
soluble in  water,  slightly  soluble  in  cold  alcohol, 
soluble  in  3.3  parts  of  boiling  alcohol. 

It  may  be  identified  by  a  test  in  which  the 
compound  is  hydrolyzed  with  sodium  hydroxide, 
and  the  resulting  hydroquinone  oxidized  with 
hydrogen  peroxide  to  menadione;  tests  are  then 
applied  for  both  acetate  and  menadione. 

The  melting  point  of  acetomenaphthone  is  be- 
tween 112°  and  115°.  The  absorbancy  of  a  0.003 
per  cent  w/v  solution  in  dehydrated  alcohol,  at 
285  m\i,  is  between  0.69  and  0.78.  One  Gm.  con- 
tains no  more  zinc  than  corresponds  to  0.2  mg.  of 
zinc  sulfate.  When  dried  to  constant  weight  at  80° 
the  loss  in  weight  is  not  over  1.0  per  cent.  The 
limit  of  sulfated  ash  is  0.1  per  cent. 

Assay. — A  sample  of  about  200  mg.  of  aceto- 
menaphthone is  boiled  with  a  mixture  of  15  ml. 
of  glacial  acetic  acid  and  15  ml.  of  diluted  hydro- 
chloric acid,  under  a  reflux  condenser,  for  15 
minutes  to  remove  the  acetate  groups  by  hydrol- 


ysis; the  resulting  hydroquinone  is  quantitatively 
oxidized  to  quinone  by  titration  with  0.05  N  eerie 
ammonium  sulfate,  using  o-phenanthroline-ferrous 
complex  as  indicator.  A  second  titration  is  per- 
formed in  the  same  manner,  except  that  the 
sample  is  omitted  and  that  the  solution  is  not 
heated;  this  corrects  for  any  reducing  substances 
in  the  reagents.  Each  ml.  of  the  difference  in  the 
volumes  of  eerie  ammonium  sulfate  solution  re- 
quired represents  6.457  mg.  of  C15H14O4;  this 
equivalent  is  based  on  two  eerie  ions  being  re- 
quired to  oxidize  the  hydroquinone  derived  from 
acetomenaphthone.  B.P. 

Uses. — Acetomenaphthone  is  intended  for  oral 
administration  in  the  treatment  or  prevention  of 
vitamin  K  deficiency  and  the  hypoprothrombinemia 
resulting  therefrom.  Its  relationship  to  menadione 
has  been  referred  to  above;  it  differs  from 
menadiol  sodium  diphosphate  (q.v.)  in  being  a 
diacetate  of  menadiol  instead  of  the  tetrasodium 
salt  of  the  diphosphate  of  menadiol. 

Ansbacher  and  colleagues  (J.A.C.S.,  1939,  61, 
1924;  1940,  62,  155)  observed  that  several  de- 
rivatives of  2 -methyl- 1,4-naphthohydroquinone 
(referred  to  as  menadiol)  exert,  in  lower  animals, 
the  typical  effect  of  the  K  vitamers  in  restoring 
coagulability  of  the  blood  in  animals  suffering 
from  vitamin  K  deficiency.  They  found  that 
menadiol  diacetate  (acetomenaphthone)  had  to 
be  given  in  about  twice  the  dose  of  menadione  to 
produce  the  same  degree  of  therapeutic  effect. 
Fieser  et  al.  (J.  Biol.  Chem.,  1941,  137,  680) 
estimated  the  antihemorrhagic  potency  of  aceto- 
menaphthone to  be  about  one-third  that  of 
menadione.  Since  the  toxic  dose  of  acetomenaph- 
thone is  more  than  three  times  as  large  as  that 
of  menadione  (Ansbacher  et  al.,  J.  Pharmacol., 
1942,  75,  111),  the  ratio  of  efficacy  to  toxicity 
is  better  for  acetomenaphthone  than  for  mena- 
dione. Ewing  et  al.  (J.  Biol.  Chem.,  1939,  131, 
345)  called  attention  to  a  further  advantage  of 
acetomenaphthone  in  not  being  adversely  affected 
by  light,  as  is  the  case  with  menadione. 

Fantl  et  al.  (Australian  J.  Exp.  Bio.  Med.  Sc, 
1951,  29,  433)  found  that  the  presence  of  bile  in 
the  intestine  is  not  essential  for  enteric  absorption 
of  acetomenaphthone;  they  proposed  a  test  of 
vitamin  K  deficiency  based  on  urinary  excretion 
of  the  drug  following  an  oral  dose  of  50  to  60  mg., 
the  excretion  in  the  normal  individual  exceeding 
15  per  cent  of  the  ingested  dose  in  24  hours. 
Douglas  and  Brown  (Brit.  M.  J.,  1952,  1,  412) 
found  acetomenaphthone  to  be  less  effective  than 
vitamin  Ki  (phytonadione)  in  correcting  the 
hypoprothrombinemia  induced  by  Tromexan. 

The  dose  of  acetomenaphthone  is  2  to  10  mg. 
(approximately  1/30  to  1/6  grain)  by  mouth  daily. 

The  B.P.  recognizes  Tablets  of  Acetomenaph- 
thone, requiring  not  less  than  92.5  per  cent  and 
not  more  than  107.5  per  cent  of  the  labeled 
amount  of  C15H14O4. 

ACETONE.    N.F. 

Dimethyl  Ketone,  [Acetonum] 
CH3.CO.CH3 

"Acetone  contains  not  less  than  99  per  cent  of 
CaHeO."  N.F. 


12 


Acetone 


Part  I 


Dimethylketone;  Diraethylketal;  Propanone;  Pyroacetic 
Ether.  Fr.  Acetone.  Ger.  Azeton ;  Essiggeist;  Mesitalkohol. 
Sp.  Acetona. 

Acetone  is  found  in  small  amount  in  normal 
urine,  in  blood,  etc.,  and  in  larger  amount  in  cer- 
tain pathological  conditions.  It  is  a  product  of  the 
dry  distillation  of  sugar,  gum,  cellulose,  etc. 

Acetone  may  be  made  in  commercial  quan- 
tities by  the  dry  distillation  of  calcium  acetate  at 
a  temperature  not  exceeding  300°.  The  crude 
acetone  thus  obtained  may  be  purified  by  digestion 
with  quicklime  and  again  distilled  from  sodium 
hydroxide.  During  the  first  World  War  the  large 
demand  for  acetone  led  to  the  development  of  a 
process  in  which  corn  starch  was  fermented  by 
Clostridium  acetobutylicum  Weizmann.  yielding 
butyl  alcohol,  acetone,  and  ethyl  alcohol.  Later  a 
process  was  developed  in  which  the  Bacillus  aceto- 
ethylicitm  was  employed;  this  resulted  in  the 
formation  of  acetone  and  ethyl  alcohol.  Today 
both  processes,  in  many  different  modifications, 
are  in  use;  the  raw  materials  include  a  wide 
variety  of  carbohydrates,  especially  molasses,  but 
including  also  potatoes,  Jerusalem  artichokes  and 
plant  wastes  rich  in  pentosans  (corn  stalks,  wheat 
and  rye  bran,  etc.) ;  for  a  review  of  the  recent 
production  status  see  hid.  Eng.  Cliem.,  1952,  44, 
1677.  Acetone  has  also  been  produced  commer- 
cially starting  with  propylene  made  from  petro- 
leum, and  it  can  be  prepared  catalytically  from 
ethanol. 

Description. — "Acetone  is  a  transparent, 
colorless,  mobile,  volatile  liquid,  having  a  char- 
acteristic odor.  A  solution  of  Acetone  (1  in  2)  is 
neutral  to  litmus.  Acetone  is  miscible  with  water, 
with  alcohol,  with  ether,  with  chloroform,  and 
with  most  volatile  oils.  The  specific  gravity  of 
Acetone  is  not  more  than  0.789,  indicating  not 
less  than  99  per  cent  of  C3H6O.  Acetone  distils 
between  55.5°  and  57°." 

Standards  and  Tests. — Identification. — (1) 
A  yellow  precipitate  of  iodoform  is  obtained  on 
adding  a  few  ml.  of  iodine  T.S.  to  a  warm  mixture 
of  1  ml.  of  sodium  hydroxide  T.S.  and  1  ml.  of  a 
1  in  200  aqueous  solution  of  acetone.  (2)  A  deep 
red  color  is  produced  when  1  ml.  of  a  1  in  200 
aqueous  solution  of  acetone  is  mixed  with  5  drops 
of  sodium  nitroprusside  T.S.  and  2  ml.  of  sodium 
hydroxide  T.S.,  then  acidified  slightly  with  acetic 
acid;  on  diluting  the  mixture  with  several  volumes 
of  distilled  water  a  violet  tint  develops.  Non- 
volatile residue. — Not  over  2  mg.  from  50  ml.  of 
acetone,  evaporated  in  a  tared  porcelain  dish  on  a 
water  bath  and  dried  at  105°  for  1  hour.  Readily 
oxidizable  substances. — A  mixture  of  20  ml.  of 
acetone  and  0.1  ml.  of  0.1  N  potassium  per- 
manganate is  not  decolorized  within  15  minutes. 
N.F. 

Distilled  with  water  and  chlorinated  lime,  ace- 
tone yields  nearly  twice  its  weight  of  chloroform, 
and  hence  is  largely  used  to  produce  the  latter. 

Uses. — Acetone  is  used  chiefly  as  a  solvent, 
especially  for  fats,  resins,  camphors,  and  pyroxy- 
lin; it  was  employed  as  a  menstruum  for  ex- 
tracting oleoresins  in  U.S. P.  VIII.  It  is  sometimes 
included  in  the  formulation  of  topically  applied 
antiseptic  solutions  to  facilitate  penetration  and 


intimate  contact  with  the  skin,  and  to  hasten 
evaporation  of  the  solvent  following  application 
of  the  solution.  Some  physicians  use  it  in  prefer- 
ence to  ethyl  alcohol  for  cleansing  the  skin  in 
preparation  for  smallpox  vaccination.  Prolonged 
or  repeated  contact  of  acetone  with  the  skin  causes 
erythema  and  dryness.  Acetone  is  used  as  the  de- 
naturing ingredient  in  some  formulas  for  denatured 
alcohol. 

In  a  general  way,  the  physiological  effects  of 
acetone  seem  to  resemble  those  of  alcohol.  The 
metabolism  of  acetone  was  reported  by  Price  and 
Rittenberg  (/.  Biol.  Chem.,  1950.  185,  449 j;  the 
fate  of  acetone  labeled  with  the  radioactive  isotope 
C14  was  reported  by  Sakami  and  Lafaye  {ibid., 
1951,  193,  199).  Koehler  et  al.  (ibid.,  1941,  140, 
811)  gave  intravenous  injections  of  acetone  at 
the  rate  of  5  Gm.  per  hour  to  human  subjects 
without  any  symptomatic  effects  other  than  slight 
drowsiness.  The  rate  of  acetone  breakdown  as 
judged  from  blood  levels  and  urinary  excretion 
was  extremely  slow.  Data  on  respiratory  excretion 
of  acetone  were  reported  by  Henderson  et  al. 
(Diabetes,  1952,  1,  188). 

A  liver  function  test  employing  an  intravenous 
injection  of  40  ml.  of  a  5  per  cent  solution  of 
acetone  containing  1  Gm.  of  sodium  bicarbonate, 
followed  by  a  determination  of  the  blood  acetone 
level  after  12  hours,  was  described  by  Schumann 
and  Klotzbucher  (Klin.  Wcknschr.,  1940,  19, 
1101). 

The  industrial  hazard  to  health  from  exposure 
to  acetone  has  been  studied  by  Haggard  et  al. 
(J.  Indust.  Hyg.  Toxicol.,  1944,  26,  133).  In- 
halation of  vapors  of  acetone  will  cause  headache, 
excitement,  and  fatigue;  at  high  concentrations 
unconsciousness  and  narcosis  mav  result  (Chatter- 
ton  and  Elliot.  J. A.M. A.,  1946, 'l30,  1222).  The 
patient  should  have  access  to  fresh  air,  and  oxygen 
inhalation  and  stimulants  should  be  employed  if 
required.  Albertoni  found  that  doses  of  15  to  20 
Gm.  of  acetone  produced  no  symptoms  in  man 
beyond  slight  narcosis. 

Storage. — Preserve  "in  tight  containers,  re- 
mote from  fire."  N.F. 

Off.  Prep. — Surgical  Merbromin  Solution; 
Xitromersol  Tincture;  Thimerosal  Tincture,  N.F. 

ACETOPHENETIDIN.     U.S.P.  (B.P.,  LP.) 

Acetphenetidin,  Phenacetin,  [Acetophenetidinum] 


C2H50 


NH-C0-CH3 


The  B.P.  defines  Phenacetin  as  aceto-/>-phenet- 
idide,  while  the  LP.  defines  it  as  aceto-4-phenet- 
idine. 

B.P.,  LP.  Phenacetin,  Phenacetinum.  Para-acetphenet- 
idine;  Para-acetaminophenetol.  Acetphenetidinum ;  Ethoxy- 
para-acetanilidum;  Acethylphenetidina;  Acethylphenet- 
idinum.  Fr.  Ethoxypara-acetanilide ;  Phenedine;  Phenine. 
Ger.  Phenazetin.  It.  Acetilfenetidina.  Sp.  Acetilfeneti- 
dina ;    Acetofenetidina;   Fenedina;    Fenina;    Fenacetina. 

Acetophenetidin  may  be  manufactured  by  any 
one  of  several  processes,  the  choice  of  the  method 
depending  on  the  availability  of  the  respective 
starting  materials  and  the  economy  of  their  utili- 


Part  I 


Acetophenetidin  Tablets  13 


zation.  In  one  process  phenol  is  converted  to  a 
mixture  of  ortho-  and  />ara-nitrophenol ;  the 
former,  which  is  not  utilizable,  is  removed  by  dis- 
tillation with  steam.  The  sodium  derivative  of 
the  />ara-nitrophenol  is  treated  with  ethyl  chloride 
or  ethyl  bromide,  producing  ethyl  />-nitrophenol 
or  p-nitrophenetol,  C6H4(N02jOC2H5.  This  is 
reduced  with  sodium  sulfide  or  with  iron  filings 
and  hydrochloric  acid  to  p-phenetidin,  CeHU- 
(NH2)OC2Ho.  Glacial  acetic  acid  or  any  other 
acetylating  agent  is  used  to  introduce  the  acetyl 
group,  producing  />-acetophenetidin.  Monochloro- 
benzene,  normally  less  costly  than  phenol,  may 
also  be  employed  as  the  starting  point  for  the 
synthesis  of  acetophenetidin;  by  nitration  £-chlo- 
ronitrobenzene  is  obtained  and  this,  by  treatment 
with  alkali,  is  converted  to  p-nitrophenol  which  is 
treated  as  described  above.  Acetophenetidin  may 
also  be  prepared  from  />-acetaminophenol  by 
ethylation.  In  still  another  method  acetophenet- 
idin is  obtained  by  the  action  of  the  gas  ketene, 
CH2=CO,  on  />-phenetidin  dissolved  in  acetone 
or  other  inert  solvent. 

Description.  —  "Acetophenetidin  occurs  as 
white,  glistening  crystals,  usually  in  scales,  or  as 
a  fine,  white,  crystalline  powder.  It  is  odorless, 
has  a  slightly  bitter  taste,  and  is  stable  in  air.  Its 
saturated  solution  is  neutral  to  litmus.  One  Gm. 
of  Acetophenetidin  dissolves  in  about  1300  ml.  of 
water,  in  15  ml.  of  alcohol,  in  15  ml.  of  chloro- 
form, and  in  about  130  ml.  of  ether.  One  Gm.  of 
Acetophenetidin  dissolves  in  85  ml.  of  boiling 
water,  and  in  about  3  ml.  of  boiling  alcohol. 
Acetophenetidin  melts  between  134°  and  136°." 
U.S.P. 

Standards  and  Tests. — Identification. — A 
ruby  red  color  slowly  develops  when  200  mg. 
acetophenetidin  is  boiled  for  1  minute  with  1  ml. 
of  hydrochloric  acid,  diluted  with  10  ml.  of  water, 
cooled,  filtered,  and  1  drop  of  potassium  dichro- 
mate  T.S.  added  to  the  filtrate.  Loss  on  drying. — 
Not  over  0.5  per  cent  on  drying  at  60°  for  1  hour. 
Residue  on  ignition. — Not  over  0.05  per  cent. 
Readily  carbonizable  substances. — A  solution  of 
500  mg.  of  acetophenetidin  in  5  ml.  of  sulfuric 
acid  has  no  more  color  than  matching  fluid  T. 
Acetanilid. — Neither  turbidity  nor  precipitation 
results  when  bromine  T.S.  is  added,  dropwise,  to 
the  filtrate  from  a  mixture  of  500  mg.  of  aceto- 
phenetidin and  10  ml.  of  water  which  has  been 
boiled  for  1  minute,  then  cooled  and  filtered. 
U.S.P. 

Incompatibilities. — Acetophenetidin  is  slowly 
decomposed  by  strong  acids  and  alkalies;  oxidiz- 
ing agents  usually  produce  a  red  color;  ethyl  ni- 
trite spirit  causes  the  slow  development  of  a  yel- 
low color  which  deepens  to  reddish  brown.  It 
forms  a  wet  mass  when  triturated  with  chloral 
hydrate,  acetylsalicylic  acid,  aminopyrine,  and 
many  other  substances.  An  insoluble  derivative  is 
formed  with  iodine. 

Uses. — Acetophenetidin  is  useful  as  an  anti- 
pyretic and  analgesic  in  the  same  group  of  cases 
in  which  acetanilid  is  of  service.  It  is  commonly 
prescribed  in  combination  with  other  drugs  such 
as  acetylsalicylic  acid  or  acetanilid,  caffeine  or 
citrated  caffeine,  and  codeine  sulfate,  etc.  Aceto- 


phenetidin, like  acetanilid,  yields  in  the  body 
N-acetyl-p-aminophenol  and  its  physiological  ac- 
tion and  therapeutic  effects  are  essentially  the 
same  as  those  of  acetanilid  (q.  v.)  Its  action, 
however,  is  more  gradual  and  more  prolonged  and 
it  is  less  likely  to  give  rise  to  undesirable  symp- 
toms. Only  7  of  the  62  cases  of  sulfhemoglob- 
inemia  reported  by  Brandenburg  and  Smith  (see 
under  Acetanilid)  were  associated  with  prolonged 
use  of  acetophenetidin,  as  compared  to  the  44 
cases  reported  from  the  prolonged  use  of  ace- 
tanilid. The  same  increase  in  the  threshold  to  the 
pain  produced  by  radiant  heat  was  observed  by 
Wolff,  Hardy  and  Goodell  with  an  oral  dose  of 
300  mg.  of  acetophenetidin  as  was  produced  by 
300  mg.  of  acetanilid.  The  Food  and  Drug  Ad- 
ministration believes  that  acetophenetidin  may  be 
a  dangerous  drug  if  the  daily  dose  exceeds  1  Gm. 
and  has  expressed  the  following  opinion:  "It  is 
well  established  that  frequent  or  continued  use  of 
acetophenetidin-containing  preparations  may  be 
dangerous,  causing  serious  blood  disturbances. 
This  fact  should  be  borne  in  mind  in  devising  la- 
bels for  this  preparation  to  conform  with  the  re- 
quirement of  section  502  (f)(2)  of  the  Act  that 
the  labeling  of  drugs  bear  adequate  warnings." 
{Drug  &  Cosmetic  Ind.,  1941,  48,  163.)  S 

The  usual  dose  of  acetophenetidin  is  300  mg. 
(approximately  5  grains),  with  a  range  of  300  mg. 
to  1  Gm.  A  total  dose  in  24  hours  up  to  3  Gm.  has 
been  reported  (but  see  above). 

Storage. — Preserve  "in  well-closed  contain- 
ers." U.S.P. 

ACETOPHENETIDIN  TABLETS. 
U.S.P.  (B.P.,  LP.) 

[Tabellae  Acetophenetidini] 

"Acetophenetidin  Tablets  contain  not  less  than 

94  per  cent  and  not  more  than  106  per  cent  of 
the  labeled  amount  of  C10H13O2N."  U.S.P.  The 
B.P.  requires  that  Tablets  of  Phenacetin  contain 
not  less  than  95.0  per  cent,  and  not  more  than 
105.0  per  cent,  of  the  stated  amount  of  phe- 
nacetin. The  tablets  may  be  prepared  by  moist 
granulation  and  compression.  The  LP.  limits  are 
94.0  and  106.0  per  cent,  respectively. 

B.P.  Tablets  of  Phenacetin;  Tabellae  Phenacetini.  LP. 
Compressi  Phenacetini.  Sp.  Tabletas  de  Acetofenetidina. 

Assay. — A  representative  sample  of  tablets, 
equivalent  to  about  300  mg.  of  acetophenetidin, 
is  extracted  with  petroleum  benzin  to  remove 
lubricants,  then  with  chloroform  to  dissolve  aceto- 
phenetidin. The  chloroform  is  evaporated  and  the 
residue  of  acetophenetidin  is  dried  at  60°  and 
weighed.  U.S.P. 

In  the  B.P.  assay  the  phenacetin  is  extracted 
from   a   sample    of   powdered   tablets   with   hot 

95  per  cent  alcohol,  the  solution  is  evaporated 
and  the  residue  washed  with  successive  5-ml.  por- 
tions of  water,  previously  saturated  with  phenace- 
tin. The  washed  residue  is  redissolved  in  hot  95 
per  cent  alcohol,  the  solution  evaporated  and  the 
residue  dried  to  constant  weight  at  105°. 

Usual  Sizes. — 1,  2,  3,  and  5  grains  (approxi- 
mately 60,  120,  200,  and  300  mg.). 


14  Acetophenetidin   and   Phenyl   Salicylate  Tablets 


Part  I 


ACETOPHENETIDIN    AND    PHENYL 
SALICYLATE  TABLETS.     N.F. 

Phenacetin  and  Salol  Tablets 
[Tabellae  Acetophenetidini  et  Phenylis  Salicylates] 

"Acetophenetidin  and  Phenyl  Salicylate  Tablets 
contain  not  less  than  90  per  cent  and  not  more 
than  110  per  cent  of  the  labeled  amounts  of 
acetophenetidin  and  of  phenyl  salicylate."  N.F. 

Tests. — Identification. — (1)  The  tablets  re- 
spond to  the  identification  tests  under  Phenyl 
Salicylate  Tablets.  (2)  A  purplish  color  is  pro- 
duced when  powdered  tablets  equivalent  to  about 
100  mg.  of  acetophenetidin  is  boiled  for  1  minute 
with  1  ml.  of  hydrochloric  acid,  diluted  with  10 
ml.  of  water,  cooled,  filtered,  and  1  drop  of  po- 
tassium dichromate  T.S.  added  to  the  filtrate. 
N.F. 

Assay. — For  acetophenetidin. — A  representa- 
tive portion  of  tablets,  equivalent  to  not  more 
than  80  mg.  of  phenyl  salicylate,  is  extracted  with 
chloroform  to  dissolve  both  the  acetophenetidin 
and  the  phenyl  salicylate.  The  chloroform  is 
evaporated  and  the  residue  is  heated  for  15  min- 
utes with  2.5  per  cent  sodium  hydroxide  solution 
which  hydrolyzes  phenyl  salicylate  to  sodium 
phenolate  and  sodium  salicylate,  but  does  not 
affect  acetophenetidin.  The  latter  is  extracted 
with  chloroform  and,  after  washing  each  of  the 
chloroform  portions  with  water,  the  solvent  is 
evaporated  and  the  acetophenetidin  dried  at  60° 
for  1  hour  and  weighed.  For  phenyl  salicylate. — 
The  alkaline  solution  and  aqueous  washings  re- 
maining after  the  extraction  of  acetophenetidin 
is  analyzed  as  directed  under  the  assay  for  Phenyl 
Salicylate  Tablets.  N.F. 

Storage. — Preserve  "in  tight  containers  at  a 
temperature  not  above  35°."  N.F. 

Usual  Size. — These  tablets  usually  contain 
2^2  grains  (approximately  150  mg.)  of  each  in- 
gredient. 

ACETRIZOIC  ACID.    U.S.P. 

3-Acetamido-2,4,6-triiodobenzoic  Acid 


NH-CO-CH3 


"Acetrizoic  Acid  contains  not  less  than  99  per 
cent  of  C9H6I3NO3.  and  not  less  than  67  per 
cent  and  not  more  than  68.5  per  cent  of  iodine 
(I),  calculated  on  the  dried  basis."  U.S.P. 

Acetrizoic  acid  is  the  active  component  of  so- 
dium acetrizoate  injection  (Urokon,  Mallinck- 
rodt),  a  radiopaque  medium  described  in  a 
separate  monograph.  The  acid  is  prepared  by  re- 
ducing ra-nitrobenzoic  acid  to  w-aminobenzoic 
acid,  treating  with  iodine  monochloride  to  pro- 
duce 2,4,6-triiodobenzoic  acid,  and  finally  acetyl- 
ating  with  acetic  anhydride  (Wallingford, 
J.A.Ph.A.,  1953,  42,  721).  For  detailed  informa- 
tion see  U.  S.  Patent  2,611,786  (1952). 

Description. — "Acetrizoic  Acid  occurs  as  a 
white  powder.  It  is  odorless.  Acetrizoic  Acid  is 


slightly  soluble  in  water.  It  is  soluble  in  alcohol, 
slightly  soluble  in  ether,  very  slightly  soluble  in 
chloroform,  and  practically  insoluble  in  benzene. 
It  is  soluble  in  solutions  of  alkali  hydroxides. 
Acetrizoic  Acid  melts  with  decomposition  between 
278°  and  283°."  U.S.P. 

Standards  and  Tests. — Identification. — (1) 
On  heating  acetrizoic  acid  the  substance  melts  to 
a  dark  brown  liquid  and  liberates  iodine  vapors. 
(2)  After  preliminary  hydrolysis  of  acetrizoic 
acid  with  alkali,  followed  by  diazotization  and 
coupling  with  betanaphthol,  a  white  precipitate, 
which  becomes  purple  within  5  minutes,  is  pro- 
duced. Loss  on  drying. — Not  over  0.1  per  cent, 
when  dried  at  105°  for  18  hours.  Heavy  metals. — 
The  limit  is  20  parts  per  million.  U.S.P. 

Assay. — For  acetrizoic  acid. — An  alcohol  solu- 
tion of  1  Gm.  of  acetrizoic  acid  is  titrated  with 
0.1  N  sodium  hydroxide,  using  phenolphthalein 
as  indicator.  Each  ml.  of  0.1  N  sodium  hydroxide 
represents  55.69  mg.  of  C9H6I3NO3.  For  iodine. 
— The  assay  for  iodine  specified  for  Iodophthalein 
Sodium  is  employed.  U.S.P. 

For  information  concerning  the  ultimate  use  of 
this  agent,  in  the  form  of  its  sodium  salt,  see 
under  Sodium  Acetrizoate  Injection. 

Storage. — Preserve  "in  well-closed  containers." 
U.S.P. 

ACETYLCHOLINE  CHLORIDE.     LP. 

Acetylcholine  Chloridum 

CH3.COOCH2.CH2.N(CH3)3Cl 

Acetylcholine  chloride  is  2-acetoxyethyltri- 
methylammonium  chloride;  it  contains  not  less 
than  98.0  per  cent,  and  not  more  than  the  equiva- 
lent of  102.0  per  cent,  of  C7H16O2NCI,  calculated 
with  reference  to  the  substance  dried  to  constant 
weight  at  110°.  LP. 

Acecoline  (Anglo-French  Laboratories) 

Acetylcholine  occurs  naturally  in  many  tissues 
(see  below)  but  for  pharmacological  experimenta- 
tion and  therapeutic  use  it  is  prepared  syntheti- 
cally, as  the  chloride  salt.  In  the  method  most 
commonly  used  trimethylammonium  chloride  is 
interacted  with  ethylene  oxide  to  form  choline 
chloride,  which  is  treated  with  acetic  anhydride 
to  form  acetylcholine  chloride. 

Description. — Acetylcholine  chloride  occurs 
as  white,  odorless,  very  hygroscopic  crystals.  It 
is  very  soluble  in  water,  in  alcohol,  in  chloroform, 
and  in  acetic  acid;  it  is  insoluble  in  ether  and  in 
benzene.  Acetylcholine  chloride,  after  drying  at 
110°,  melts  between  149°  and  152°. 

Standards  and  Tests.— Identification. — (1) 
Trimethylamine,  recognizable  by  its  odor,  is 
evolved  when  acetylcholine  chloride  is  heated  with 
sodium  hydroxide  T.S.  (2)  An  aqueous  solution 
of  acetylcholine  chloride  yields  a  precipitate  with 
phosphotungstic  acid  T.S.,  with  trinitrophenol 
T.S.,  and  with  iodine  T.S.  (3)  It  responds  to  tests 
for  chloride  and,  after  alkaline  hydrolysis,  to  tests 
for  acetate.  Reaction. — A  10  per  cent  w/v  solu- 
tion in  water  is  neutral  to  litmus  T.S.  Arsenic. — 
The  limit  is  2  parts  per  million.  Heavy  metals  — 
The  limit  is  10  parts  per  million.  Lead. — The  limit 
is  10  parts  per  million.  Free  acid. — Not  more  than 


Part  I 


Acetylsalicylic  Acid  15 


0.2  ml.  of  0.01  N  sodium  hydroxide  produces  a 
red  color  in  a  solution  of  100  mg.  of  acetylcholine 
chloride  in  10  ml.  of  recently  boiled  and  cooled 
water  to  which  1  drop  of  phenolphthalein  T.S.  has 
been  added.  Trimethylamine. — No  odor  of  that 
substance  is  apparent  on  boiling  a  solution  of 
100  mg.  of  acetylcholine  chloride  in  10  ml.  of 
saturated  solution  of  sodium  carbonate.  Loss  on 
drying. — Not  over  0.75  per  cent  when  dried  to 
constant  weight  at  110°.  Residue  on  ignition. — 
Not  over  0.1  per  cent.  LP. 

Assay. — About  100  mg.  of  acetylcholine  chlo- 
ride, dissolved  in  boiled  and  cooled  distilled  water, 
is  boiled  under  reflux  for  15  minutes  with  10  ml. 
of  0.1  N  carbonate-free  sodium  hydroxide,  which 
releases  acetic  acid  by  hydrolysis.  The  excess  of 
alkali  is  titrated  with  0.1  N  sulfuric  acid,  using 
phenolphthalein  T.S.  as  indicator.  Each  ml.  of 
0.1  N  sodium  hydroxide  represents  18.17  mg.  of 
C7H16O2NCI.  LP. 

Action  of  Acetylcholine. — Acetylcholine, 
CH3.COOCH2.CH2N(CH3)30H,  is  now  gener- 
ally considered  to  be  the  chemical  mediator  of 
the  parasympathetic  postganglionic,  the  auto- 
nomic (sympathetic  and  parasympathetic)  pre- 
ganglionic and  motor  nerve  impulses.  When  one 
of  these  nerves,  as  for  example  the  vagus,  is 
stimulated,  there  is  formed  at  the  peripheral  ter- 
minations a  substance  which  appears  to  be  acetyl- 
choline, and  which  is  generally  believed  to  act 
upon  the  parenchyma  of  the  organ  under  consid- 
eration (see  under  Parasympathomimetic  Agents 
and  Cholinesterase  Inhibitors).  After  excitation 
of  the  nerve  ceases  there  is  a  rapid  breakdown  of 
the  compound,  effected  by  the  presence  of  the 
enzyme  cholinesterase  (see  Koppanyi  and  associ- 
ates, /.  Pharmacol,  1953,  107,  482,  501).  As  a 
result  of  this  enzyme-catalyzed  hydrolytic  action, 
the  acetyl  radical  is  split  off,  leaving  choline, 
which  is  comparatively  inert. 

If  acetylcholine  is  injected  into  the  circulation 
it  will  cause  all  the  characteristic  effects  of  elec- 
trical stimulation  of  all  the  parasympathetic 
nerves,  such  as  slowing  of  the  pulse,  vasodilata- 
tion, fall  in  blood  pressure,  bronchospasm,  in- 
creased bronchial  secretion,  hyperpnea,  increased 
gastric  secretion,  increased  tone  and  peristaltic 
contractions  of  the  gastrointestinal  tract,  increased 
secretion  of  sweat,  tears  and  saliva,  contraction 
of  pupils,  etc.  (Koppanyi,  Bull.  Johns  Hopkins 
Hosp.,  1948,  83,  532).  In  larger  doses,  acetyl- 
choline excites  the  sympathetic  ganglia,  producing 
a  very  definite  group  of  reactions  which  resemble 
those  of  nicotine.  Large  doses  of  acetylcholine 
also  cause  reactions  of  the  voluntary  muscles. 
This  contraction  of  skeletal  muscle  has  led  to  the 
basic  concept  of  cholinergic  (acetylcholine)  me- 
diation of  motor  impulses  to  skeletal  muscles  (see 
under  Curarimimetic  Agents) ;  for  further  infor- 
mation see  Feldberg,  Physiol.  Rev.,  1945,  25, 
596,  also  Lorente  de  No,  Bull.  Johns  Hopkins 
Hosp.,  1948,  83,  497).  Welsh  {ibid.,  568)  con- 
cluded that  acetylcholine  acts  on  all  cells  of  the 
body  to  alter  the  excitability  of  the  cell  through 
change  of  membrane  polarity  and  permeability. 
Acetylcholine  is  also  important  in  the  transmission 
of  the  nerve  impulse  along  the  axone  (Nachman- 
sohn,  ibid.,  1948,  83,  463). 


Uses. — Acetylcholine  has  been  employed  to 
some  extent  as  a  therapeutic  remedy  in  various 
acute  conditions  in  which  stimulation  of  the  au- 
tonomic nervous  system  is  desirable.  It  has  been 
used  for  tobacco  amblyopia  (Duggan,  J.A.M.A., 
1937,  109,  1354),  paroxysmal  auricular  tachy- 
cardia (Abbott,  ibid.,  1939,  113,  1243),  acropares- 
thesia (Ekbom,  Acta  psychiat.  neurol.,  1939,  14, 
311),  and  paralytic  ileus  (Abel,  Lancet,  1933,  2, 
1252).  The  extreme  evanescence  of  its  action  and 
the  marked  stimulation  of  the  autonomic  ganglia 
from  overdoses  have  greatly  restricted  its  value. 
Methacholine  chloride  and  carbachol  are  gener- 
ally preferred.  Drugs  which  inhibit  cholinesterase, 
such  as  neostigmine  and  physostigmine,  are  more 
widely  used.  S 

The  dose  of  acetylcholine  chloride  is  50  mg. 
initially,  then  100  mg.  daily,  subcutaneously  or 
intramuscularly.  At  the  most,  200  mg.  (approxi- 
mately 3  grains)  is  given.  It  should  not  be 
administered  intravenously  because  less  than 
one-tenth  these  quantities  will  cause  marked 
physiological  reactions.  When  using  the  drug  it 
is  advisable  to  have  a  solution  of  atropine  ready 
for  immediate  administration  if  it  is  necessary  to 
counteract  the  effects  of  acetylcholine. 

Acetylcholine  chloride,  because  of  its  pro- 
nounced hygroscopicity  and  the  instability  of  its 
aqueous  solutions,  is  supplied  in  ampuls  contain- 
ing 100  mg.  of  the  crystals,  from  which  a  solution 
may  be  prepared  as  required.  Under  the  name 
Acecoline  a  propylene  glycol  solution  containing 
in  1  ml.  20  mg.,  50  mg.,  100  mg.,  or  200  mg.,  with 
saligenin,  is  also  marketed. 

Storage. — Acetylcholine  chloride  should  be 
kept  in  a  tightly-closed  container.  LP. 

ACETYLSALICYLIC  ACID. 
U.S.P.,  B.P.,  LP. 

Aspirin,  [Acidum  Acetylsalicylicum] 


C00H 


O-CO-CH3 


"Acetylsalicylic  Acid,  dried  over  sulfuric  acid 
for  5  hours,  contains  not  less  than  99.5  per  cent  of 
CoHsOi."  U.S.P.  The  B.P.  assay  rubric  is  the 
same,  but  the  chemical  is  not  required  to  be  dried. 
The  LP.,  which  defines  the  compound  as  2-acet- 
oxybenzoic  acid,  likewise  requires  not  less  than 
99.5  per  cent  purity,  the  substance  not  being 
dried. 

Fr.  Acide  acetylsalicylique ;  Aspirine.  Ger.  Acetylsali- 
zylsaure.    It.    Acido    acetilsalicilico.     Sp.    Acido     acetil- 

salicilico;  Acido  salicilacetico;  Aspirina. 

Acetylsalicylic  acid  had  been  synthesized  some 
years  before  it  was  introduced  into  medicine,  in 
1899,  by  Dreser.  The  name  aspirin,  by  which  this 
substance  is  popularly  known,  is  not  purely  fanci- 
ful nor  arbitrary.  It  is  derived  from  the  fact  that 
salicylic  acid,  as  originally  obtained  from  Spiraa 
ulmaria,  was  at  first  known  as  acidum  spiricum. 
Acetylsalicylic  acid  may  be  prepared  by  acetyliz- 
ing  salicylic  acid  by  means  of  acetic  anhydride  or 
acetyl  chloride,  the  former  being  the  more  fre- 
quently used  because  of  its  greater  economy.  An 


16  Acetylsalicylic   Acid 


Part   I 


excess  of  acetic  anhydride  is  heated  with  salicylic 
acid  at  a  temperature  of  about  150°  for  three 
hours;  the  excess  of  the  anhydride,  as  well  as 
acetic  acid  formed  in  the  reaction,  is  removed  by 
distillation,  and  the  residue  of  acetylsalicylic  acid 
is  purified  by  recrystallization  from  a  non-aqueous 
solvent.  Acetylsalicylic  acid  cannot  be  purified 
by  crystallization  from  water  or  solvents  contain- 
ing it  because  of  its  tendency  to  undergo  hydrol- 
ysis. It  may  be  crystallized  from  benzene,  methyl 
acetate,  chloroform,  or  strong  ethyl  or  methyl 
alcohol. 

Patents  have  been  granted  in  this  country  and 
in  Great  Britain  for  a  process  whereby  salicylic 
acid  is  dissolved  in  an  inert  solvent,  such  as  dry 
ethyl  ether,  through  which  ketene.  a  gas  having  the 
chemical  formula  CH2:CO,  is  passed  until  the 
solution  is  saturated.  Upon  evaporating  the  ether, 
needle-like  crystals  of  acetylsalicylic  acid  are  ob- 
tained. The  chemical  reaction  takes  place  accord- 
ing to  the  following  equation: 

CeEUOH.COOH  +  CH2:CO  -* 

C6H4.0(CH3CO).COOH 

Description. — "Acetylsalicylic  Acid  occurs  as 
white  crystals,  commonly  tabular  or  needle-like, 
or  as  a  white,  crystalline  powder.  It  is  odorless  or 
has  a  faint  odor.  It  is  stable  in  dry  air;  in  moist 
air  it  gradually  hydrolyzes  to  salicylic  and  acetic 
acids.  One  Gm.  of  Acetylsalicylic  Acid  dissolves 
in  about  300  ml.  of  water,  in  5  ml.  of  alcohol,  in 
17  ml.  of  chloroform,  and  in  from  10  to  15  ml.  of 
ether.  It  is  less  soluble  in  absolute  ether.  Acetyl- 
salicylic Acid  dissolves  with  decomposition  in 
solutions  of  alkali  hvdroxides  and  carbonates." 
U.S.P. 

The  B.P.  gives  the  melting  point  as  from  135° 
to  138°  C.  Considerable  variation  exists  in  the 
reported  values  of  the  melting  point  of  aspirin, 
some  investigators  claiming  it  to  be  131°  to 
132°  C..  while  others  claim  134°  to  135°  C.  Beal 
and  Szalkowski  (/.  A.  Ph.  A.,  1933,  22,  36)  be- 
lieve that  these  differences  are  due  to  the  fact  that 
some  decomposition  occurs  during  the  process  of 
heating  the  acid  to  the  melting  temperature,  and 
also  that  excessive  trituration  to  produce  a  fine 
powder  results  in  partial  decomposition.  Both 
effects  are  evidenced  by  a  lowered  melting  point. 
The  composition  of  the  glass  used  for  the  melting 
point  tube  may  influence  the  melting  point  of 
acetylsalicylic  acid;  Pyrex  glass  appears  to  be 
without  effect. 

Standards  and  Tests. — Identification. — (1) 
A  violet  red  color  is  produced  when  acetylsalicylic 
acid  is  heated  with  water  for  several  minutes, 
cooled,  and  a  drop  or  two  of  ferric  chloride  T.S. 
added.  (2)  When  500  mg.  of  acetylsalicylic  acid 
is  hydrolyzed  by  boiling  with  10  ml.  of  sodium 
hydroxide  T.S.,  the  solution  cooled  and  acidified 
with  10  ml.  of  diluted  sulfuric  acid  a  white  pre- 
cipitate of  salicylic  acid  is  obtained,  and  the  odor 
of  acetic  acid  is  developed.  If  the  mixture  is 
filtered,  and  3  ml.  of  alcohol  and  3  ml.  of  sulfuric 
acid  are  added  to  the  filtrate  an  odor  of  ethyl 
acetate  develops  on  warming  the  mixture.  Loss  on 
drying. — Acetylsalicylic  acid  loses  not  more  than 
0.5  per  cent  of  its  weight  on  drying  over  sulfuric 


acid  for  5  hours.  Residue  on  ignition. — Not  over 
0.05  per  cent.  Readily  carbonizable  substances. — 
A  solution  of  500  mg.  of  acetylsalicylic  acid  in 
5  ml.  of  sulfuric  acid  has  no  more  color  than 
matching  fluid  Q.  Chloride. — The  limit  is  140 
parts  per  million.  Sulfate. — The  limit  is  400  parts 
per  million.  Free  salicylic  acid. — The  limit  is  0.1 
per  cent.  Heavy  metals. — The  limit  is  10  parts  per 
million.  Substances  insoluble  in  sodium  carbonate 
T.S. — A  portion  of  500  mg.  of  acetylsalicylic  acid 
should  form  a  clear  solution  with  10  ml.  of  warm 
sodium  carbonate  T.S.  U.S.P. 

The  B.P.  tests  differ  from  corresponding  de- 
scriptions and  tests  of  the  U.S.P.  only  in  minor 
details,  except  that  the  former  permits  but  half 
the  amount  of  salicylic  acid  allowed  by  the  U.S.P. 
An  arsenic  limit  of  2  parts  per  million  and  a  limit 
of  lead  of  10  parts  per  million  are  provided. 

Assay. — The  U.S.P.  directs  that  about  1.5  Gm. 
of  acetylsalicylic  acid,  previously  dried  over  sul- 
furic acid  for  5  hours,  be  boiled  for  10  minutes 
with  50  ml.  of  0.5  N  sodium  hydroxide  and  the 
excess  base  determined  by  titration  with  0.5  N 
sulfuric  acid  using  phenolphthalein  as  indicator. 
In  this  assay  the  acetylsalicylic  acid  is  hydrolyzed 
to  form  the  sodium  salts  of  acetic  and  salicylic 
acids;  the  reliability  of  the  assay  is  dependent  on 
having  a  sample  which  has  not  decomposed  beyond 
the  permitted  limit.  A  residual  blank  titration  is 
performed.  Each  ml.  of  0.5  N  sodium  hydroxide 
represents  45.04  mg.  of  C9HSO4.  U.S.P. 

The  B.P.  assay  is  the  same  as  that  of  the  U.S.P. 
except  that  phenol  red  is  employed  as  indicator. 
The  LP.  assay  is  also  the  same,  phenolphthalein 
indicator  being  used. 

Incompatibilities. — Acetylsalicylic  acid  read- 
ily undergoes  hydrolysis  with  aqueous  solvents 
with  liberation  of  salicylic  and  acetic  acids.  In 
pure  water  complete  decomposition  takes  place 
in  100  days.  Acids  hasten  the  rapidity  of  such 
change.  Alkalies  and  solutions  of  alkaline  acetates 
and  citrates  dissolve  acetylsalicylic  acid,  but  the 
resulting  solutions  hydrolyze  rapidly  to  form  salts 
of  acetic  and  salicylic  acids.  The  decomposition 
may  be  retarded  somewhat  by  glycerin  and  sugar. 
Liquefaction  occurs  when  acetylsalicylic  acid  is 
triturated  with  phenyl  salicylate,  acetanilid,  aceto- 
phenetidin.  aminopyrine.,  antipyrine  and  many 
other  organic  products.  Partial  hydrolysis  occurs 
in  mixtures  of  acetylsalicylic  acid  with  hygro- 
scopic substances  or  salts  containing  water  of 
hydration.  Hydriodic  acid  is  slowly  produced  from 
iodides  and  subsequent  oxidation  by  the  air  liber- 
ates iodine. 

The  statement  that  quinine  and  acetylsalicylic 
acid  react  upon  each  other  to  form  the  poisonous 
quinotoxin  has  been  contradicted  by  the  experi- 
ments of  Sollmann.  Ruddiman  and  Lanwermeyer 
(/.  A.  Ph.  A.,  1924,  13,  1009)  experimented  with 
mixtures  of  acetylsalicylic  acid  with  basic  quinine 
and  also  the  sulfate,  bisulfate.  hydrochloride  and 
other  cinchona  alkaloids.  They  found  that  the 
mixture  with  quinine  alkaloid,  after  several 
months,  changed  to  a  brownish  red  viscid  mass  if 
exposed  to  the  light,  but  when  kept  in  the  dark 
the  change  was  less  rapid;  this  mixture  tested  on 
frogs  was  not  more  poisonous  than  the  freshly 


Part  I 


Acetyl  salicylic   Acid  17 


made  mixture  nor  than  the  equivalent  dose  of  ace- 
tylsalicylic  acid. 

It  has  been  reported  that  morphine  and  codeine 
form  poisonous  compounds  with  this  drug. 

Uses  (see  also  Salicylic  Acid  and  Sodium 
Salicylate). — The  antipyretic  effect  of  willow  bark 
was  known  to  the  ancients  and,  early  in  the  19th 
century,  salicylic  acid  was  prepared  from  salicin, 
a  glycoside  from  this  bark.  Acetylsalicylic  acid 
was  introduced  into  medicine  in  1899. 

Metabolism. — Acetylsalicylic  acid  is  absorbed 
as  such  from  the  gastrointestinal  tract  (Bradley 
et  al.,  Am.  J.  Digest.  Dis.,  1936,  3,  415)  and 
transported  throughout  the  tissues  as  the  sodium 
salt,  appearing  in  the  joints,  the  pleura,  etc.  Fol- 
lowing doses  of  10  Gm.  daily,  the  salicylate  con- 
centration in  the  blood  ranges  from  30  to  50  mg. 
per  100  ml.  {J. A.M. A.,  1945,  128,  1195).  The 
simultaneous  administration  of  sodium  bicar- 
bonate in  equivalent  dosage  decreases  the  blood 
concentration  almost  one-half  (Smull  et  al., 
J.A.M.A.,  1944,  125,  1173;  but  see  Lester  et  al, 
J.  Pharmacol,  1946,  87,  329).  About  £0  per  cent 
of  the  drug  is  excreted  in  the  urine,  making  its 
appearance  within  10  to  15  minutes  after  ingestion 
(/.  Pharmacol,  1919,  14,  25).  Excretion  is  almost 
complete  within  a  few  hours  although  traces  ap- 
pear in  the  urine  during  several  days.  In  febrile 
patients  only  60  to  70  per  cent  is  excreted.  From 
10  to  35  per  cent  of  the  ingested  acetylsalicylic 
acid  appears  in  the  urine  unchanged  or  as  the 
sodium  salt;  some  is  present  as  a  glucuronate. 
Such  urine  reduces  Benedict's  solution  and  gives 
a  violet  color  with  ferric  chloride. 

Therapeutic  Actions. — Acetylsalicylic  acid  is 
used  medicinally  for  several  purposes. 

Antipyretic. — The  antipyretic  effect  of  acetyl- 
salicylic acid  arises  from  its  action  on  the  central 
nervous  system.  Barbour  {Arch.  Int.  Med.,  1919, 
24,  617  and  624;  Physiol.  Rev.,  1921,  1,  295) 
showed  that  it  facilitates  dissipation  of  heat 
through  increased  peripheral  blood  flow,  hydration 
of  the  blood,  and  sweating.  Although  sponges  with 
tepid  water  or  alcohol  are  effective  for  the  reduc- 
tion of  temperature,  acetylsalicylic  acid  is  com- 
monly used  and  is  simpler  when  the  discomfort 
arising  from  fever  is  great,  as  in  influenza,  or  when 
prolonged  high  fever  may  be  deleterious  to  the 
general  welfare  of  the  patient.  Weakness  may  be 
aggravated  by  sweating  and  the  water  and  salt  so 
lost  should  be  replaced.  Therapeutic  doses  have 
no  effect  on  the  cardiovascular  system. 

Analgesic. — Acetylsalicylic  acid  alleviates  pain 
by  a  depressant  action  on  the  central  nervous  sys- 
tem, probably  on  the  thalamus;  Lester  et  al. 
(J.  Pharmacol,  1946.  87,  329)  believe  its  action 
to  be  exercised  mainly  by  the  unhydrolyzed  frac- 
tion in  the  plasma.  Integumental  pain  such  as 
myalgia,  arthralgia,  headache,  etc.,  responds  better 
than  does  pain  of  visceral  origin.  Although  it  has 
little  local  anesthetic  action,  acetylsalicylic  acid  is 
sometimes  employed  as  a  gargle  or  a  chewing  gum 
with  symptomatic  relief  of  sore  throat.  It  is  prob- 
ably the  most  commonly  used  analgesic,  being 
prescribed  alone  or  in  combination  with  aceto- 
phenetidin,  codeine,  caffeine,  amphetamine  and 
other  drugs. 


The  threshold  for  cutaneous  pain  through  heat 
is  increased  about  35  per  cent  within  50  to  100 
minutes  after  oral  doses  of  65  to  300  mg.,  the 
effect  lasting  for  about  2  hours.  In  comparison, 
15  mg.  of  morphine  sulfate  injected  intramuscu- 
larly increases  the  threshold  about  70  per  cent 
(Wolff,  Hardy  and  Goodell,  /.  Clin.  Inv.,  1941, 
20,  63).  Unfortunately,  evaluation  of  analgesic 
drugs  according  to  their  ability  to  depress  the 
threshold  of  pain  perception  caused  by  radiant 
heat  applied  to  the  skin  of  normal  subjects  or 
animals  has  not  been  proved  to  be  an  accurate 
prediction  of  their  efficacy  in  patients  with  pain 
due  to  injury  or  disease.  Beecher  (Science,  1952, 
116,  157)  and  his  associates  have  struggled  with 
the  evaluation  of  the  subjective  phenomenon  of 
pain  in  sick  patients.  In  attempting  to  establish 
criteria  for  effectiveness  of  an  analgesic  agent  he 
denied  the  validity  of  measuring  sensory  percep- 
tion of  pain  produced  by  heat  in  normal  subjects. 
Letters  to  the  editor  by  Hardy,  Wolff  and  Goodell 
(Science,  1953,  117,  164)  and  Beecher  (ibid., 
166)  have  debated  the  issue  to  little,  if  any,  prac- 
tical conclusion.  Ravich  (ibid.,  118,  144)  com- 
ments that  "physiological"  pain  produced  by  heat 
on  normal  tissue  is  a  normal  sensory  response 
whereas  "pathological"  pain  caused  by  disease  is 
an  abnormal  phenomenon  with  many  more  un- 
known features.  Beecher  comments  that  so-called 
"common  sense"  in  hundreds  of  years  of  clinical 
practice  has  arrived  at  an  average  effective  dose 
of  morphine  (15  mg.)  which  is  twice  as  large  as 
the  one  (8  mg.)  which  gives  essentially  maximum 
pain  relief  in  his  complicated,  controlled  studies 
of  hospital  patients.  It  can  only  be  concluded  that 
adequate  methods  of  evaluating  analgesic  drugs 
remain  to  be  developed.  Furthermore,  the  physi- 
cian is  desirous  of  relieving  pain  in  his  patient 
rather  than  using  a  dose  which  will  relieve  pain  in 
nearly  all  patients  in  the  statistical  sense  but 
which  might  fail  in  his  particular  patient. 

Acetylsalicylic  acid  relieves  the  aching  and  the 
fever  of  "grippe"  although  it  does  not  shorten  the 
course  of  the  illness. 

Antirheumatic. — Acetylsalicylic  acid  (see  also 
Sodium  Salicylate)  is  the  drug  most  generally 
employed  in  the  treatment  of  acute  rheumatic 
fever.  Larger  doses  are  administered  than  in  most 
other  conditions,  from  1  to  1.3  Gm.  (approxi- 
mately 15  to  20  grains)  being  given  hourly  until 
the  acute  joint  symptoms  are  relieved.  About  10 
doses  are  usually  required.  If  toxic  symptoms  ap- 
pear the  drug  is  discontinued  for  12  hours,  then 
given  in  doses  of  1  Gm.  every  4  hours,  six  times 
daily,  until  evidence  of  active  rheumatic  fever 
has  been  absent  for  1  week  (McEwen,  Bull  N.  Y. 
Acad.  Med.,  1943,  19,  679).  The  mechanism  of 
the  almost  specific  action  of  salicylates  in  acute 
rheumatic  fever  is  unknown;  morphine,  for  ex- 
ample, relieves  the  pain  but  not  the  swelling, 
redness  and  increased  heat  of  the  joints.  How- 
ever, salicylates  do  not  shorten  the  course  of  the 
disease  or  prevent  cardiac  and  other  complica- 
tions. There  are  general  similarities  between  the 
effects  of  salicylates  and  cortisone.  Both  relieve 
pain,  produce  a  fall  in  temperature,  reduce  the 
erythrocyte  sedimentation  rate  and  prevent  re- 


18  Acetylsalicylic   Acid 


Part   I 


lapse  of  the  rheumatic  state  as  long  as  adminis- 
tration is  continued.  Pfeiffer  (/.  Pharmacol.,  1950. 
98,  26)  demonstrated  an  increase  in  eosinophil 
count  after  administration  of  acetylsalicylic  acid. 
An  increase  in  urinary  excretion  of  reducing  ster- 
oids following  the  use  of  acetylsalicylic  acid  has 
been  reported  by  Van  Cauwenberge  (Lancet, 
1951,  260,  771;  Acta  M.  Scand.,  1952,  141,  265). 
Mild  Cushing's  syndrome  is  reported  to  have 
followed  acetylsalicylic  acid  therapy  in  acute 
rheumatic  fever  (Cochran,  Brit.  M.  J.,  1950,  2, 
1411).  Pelloja  (Lancet,  1952,  262,  233)  found 
salicylates  capable  of  inhibiting  the  action  of 
hyaluronidase  in  a  manner  similar  to  cortisone. 
Whether  these  effects  are  primary  or  are  medi- 
ated through  cortisone  release  awaits  further 
elucidation.  Actually,  in  a  large  cooperative  study 
of  the  effect  of  corticotropin,  cortisone  and  acetyl- 
salicylic acid  (Houser  et  al.,  Am.  J.  Med.,  1954. 
16,  168).  the  results  failed  to  demonstrate  supe- 
rior efficacy  for, any  of  the  3  drugs  both  as  to 
controlling  the  acute  symptoms  and  the  duration 
of  the  active  disease.  In  other  forms  of  poly- 
arthritis (gonorrheal,  streptococcal,  meningococ- 
cal, etc.)  salicvlate  therapy  induces  less  dramatic 
relief  (Cecil,  JAMA.,  1940.  114,  1443).  In  acute 
rheumatic  fever  Coburn  (Bull.  Johns  Hopkins 
Hosp.,  1943,  73,  435)  reported  excellent  results 
from  doses  of  salicylates  sufficient  to  maintain  a 
blood  concentration  of  30  to  50  mg.  per  100  ml. 
but  Wegria  and  Smull  (J. AM. A.,  1945,  129,  485) 
and  others  failed  to  confirm  the  shorter  course  of 
the  disease  and  the  decreased  incidence  of  endo- 
cardial damage.  With  doses  of  10  Gm.  or  more 
daily,  the  danger  of  salicylism  requires  careful 
observation  of  the  patient.  Salicylates  increase 
excretion  of  ascorbic  acid  (Samuels  et  al.,  J.  Phar- 
macol, 1940,  68,  465),  but  correction  of  the  de- 
ficiency permits  continuation  of  therapy. 

Acute  intraocular  inflammation  such  as  uveitis 
responds  well  to  large  doses  of  salicylates 
(JAMA.,  1920,  75,  725;  1939,  113,  928").  In 
lumbago,  pleurodynia  and  other  myalgias,  in  cer- 
tain inflammations  of  nerves  such  as  sciatica,  in 
some  instances  of  rheumatoid  arthritis  and  osteo- 
arthritis, and  in  the  host  of  similar  conditions 
which,  for  want  of  better  diagnostic  acumen,  we 
are  wont  to  call  rheumatism,  acetylsalicylic  acid 
is  a  valuable  palliative  drug. 

Action  on  the  Kidney. — A  single  dose  of  acetyl- 
salicylic acid  increases  the  renal  excretion  of  uric 
acid  by  30  to  50  per  cent  and  often  decreases  the 
concentration  of  uric  acid  in  the  blood,  an  effect 
probably  due  to  a  decrease  in  tubular  resorption 
of  uric  acid.  This  action  persists  on  repeated  ad- 
ministration if  the  diet  contains  sufficient  purines. 
Hanzlik  and  Scott  (Arch.  Int.  Med..  1917,  20, 
329)  found  albumin,  with  or  without  casts,  and 
red  and  white  cells  in  the  urine  after  doses  of 
more  than  3  Gm.  In  salicylism.  water  retention 
by  the  kidney,  manifested  by  increase  in  body 
weight  but  not  by  actual  pitting  edema,  was  also 
described.  In  current  experience,  albuminuria  and 
other  evidences  of  renal  damage  are  extremely 
rare  even  with  doses  of  6  to  10  Gm.  dailv 
(J.A.M.A.,  1945,  128,  1195).  In  gout,  acetyl'- 
salicylic  acid  in  large  doses  relieves  the  acute 
attacks  but  is  less  effective  than  colchicum.  It  is 


also  less  effective  than  cinchophen  or  probenecid 
in  the  prevention  of  recurrent  attacks  in  the  course 
of  the  disease  (Hench,  Proc.  Mayo,  1937,  12, 
262).® 

Toxicology.  Acetylsalicylic  acid  is  not  highly 
toxic.  Hopkins  (Lancet,  1945,  1,  145)  records  50 
deaths  in  England  in  5  years,  a  figure  not  unduly 
large  in  view  of  the  wide  use  of  the  drug  and  the 
large  doses  sometimes  employed  (see  also  Green- 
berg,  New  Eng.  J.  Med.,  1952,  243,  124;.  It  is 
frequently  taken  in  very  large  doses  with  suicidal 
intent  but  usually  without  success  (J.A.M.A., 
1936,  107,  276;  Ruttan,  Can.  Med.  Assoc.  J., 
1952.  67,  151).  A  single  dose  of  10  to  30  Gm.  is 
likely  to  be  fatal  although  survivals  after  larger 
doses  and  deaths  from  smaller  ones  have  been 
reported.  Impaired  renal  function  enhances  the 
toxicity.  A  total  of  12  Gm.  during  24  hours  usu- 
ally produces  symptoms  of  salicylism  such  as 
tinnitus,  vertigo,  impaired  hearing  and  headache. 
More  severe  manifestations  include  hyperpnea. 
fever  and  acidosis  and,  less  regularly,  dimness  of 
vision,  sweating,  thirst,  nausea,  vomiting,  diarrhea, 
skin  rashes,  tachycardia,  restlessness,  delirium 
and  hallucinations.  Salicylism  may  resemble  dia- 
betic or  renal  acidosis.  In  the  worst  cases,  depres- 
sion, stupor,  coma,  cardiovascular  collapse,  con- 
vulsions and  respiratory  failure  follow.  Fatal  cases 
show  diffuse  endothelial  damage  with  petechial 
hemorrhage  and  congestion  throughout  the  vis- 
cera (Troll  and  Menton,  Am.  J.  Dis.  Child.,  1945, 
69,37). 

Treatment. — Treatment  of  acute  poisoning  in- 
volves the  prompt  removal  of  the  unabsorbed 
drug  by  gastric  lavage  and  the  administration  of 
30  Gm.  of  magnesium  sulfate.  Water  and  sodium 
chloride  are  replaced  parenterally  and  intravenous 
glucose,  one-sixth  molar  sodium  r-lactate.  and 
vitamin  K  given  as  required.  High  fever  should 
be  controlled  with  tepid  sponges.  Sedation  may 
be  required  for  some  patients;  for  others  caffeine 
or  ephedrine  are  needed  to  overcome  depression. 

Complications. — Although  most  tests  of  liver 
function  show  no  abnormality,  large  doses  of 
salicylates  may  depress  the  prothrombin  activity 
of  the  blood  (Smith,  Lancet,  1951.  261,  569; 
Field,  Am.  J.  Physiol,  1949,  159,  40;  Schaeffer. 
/.  Maine  M.  A.,  1951,  42,  262).  Hemorrhagic 
tendencies  following  the  use  of  acetylsalicylic  acid 
in  post-tonsillectomv  cases  have  been  reported 
(Jones,  South.  M.  J .,  1949.  42,  124).  Decreased 
prothrombin  activity  may  also  be  responsible  in 
part  for  the  hemorrhagic  manifestations  of  sali- 
cylism and  it  may  aggravate  the  hemorrhagic 
tendencv  of  the  rheumatic  state  (Clever-Howard. 
Proc.  S.  Exp.  Biol.  Med.,  1943.  53,  234).  Hypo- 
pro  thrombinemia  is  prevented  by  simultaneous 
administration  of  1  mg.  of  menadione  for  each 
1  Gm.  of  salicvlate  (Shapiro.  JAMA.,  1944, 
125,  546:  Emerson.  JAMA.,  1952.  149,  348). 

Large  doses  of  acetylsalicylic  acid  frequently 
lead  to  gastric  distress.  Sodium  bicarbonate  may 
be  used  to  alleviate  this  distress  but  it  should  be 
pointed  out  that  its  use  may  decrease  the  blood 
concentration  of  acetylsalicylic  acid.  Various 
other  buffering  systems  are  used  to  alleviate  this 
distress,  including  aluminum  dihydroxyamino- 
acetate  and  magnesium  carbonate,  which  is  also 


Part  I 


Acetylsalicylic  Acid,  Acetophenetidin   and   Caffeine   Capsules  19 


said  to  increase  salicylate  absorption  from  the 
gastrointestinal  tract  (Paul,  J.  A.  Ph.  A.,  1950, 
39,  21;  Tebrock,  Ind.  Med.,  1951,  20,  480). 

Allergy. — Idiosyncrasy  to  acetylsalicylic  acid 
is  rare  {Am.  J.  Med.  Sc,  1940,  200,  390;  and  is 
most  frequently  observed  in  asthmatics  and  espe- 
cially in  those  with  nasal  polyps  (J.A.M.A.,  1937, 
108,  445;  Ann.  Int.  Med.,  1947,  26,  734;  Can. 
Med.  Assoc.  J.,  1951,  64,  187).  The  manifesta- 
tions are  urticaria,  erythema,  desquamative  or 
bullous  or  purpuric  skin  lesions,  angioneurotic 
edema,  laryngeal  stridor,  asthma  and  peripheral 
vascular  collapse.  These  reactions  are  often  seri- 
ous and  frequently  fatal.  Hypodermic  or  intra- 
venous epinephrine  is  usually  an  effective  treat- 
ment. In  milder  cases  antihistaminic  drugs  may 
be  useful.  As  a  test  for  sensitivity,  Duke  advised 
placing  one-eighth  of  a  tablet  in  the  mouth;  in 
hypersensitive  persons  symptoms  appear  in  one 
minute  and  the  rest  of  the  tablet  can  be  rinsed 
from  the  mouth  with  water. 

Dose. — The  usual  dose  is  600  mg.  (approxi- 
mately 10  grains)  by  mouth  every  4  hours,  as 
necessary,  with  a  range  of  300  to  900  mg.  Ordi- 
narily the  maximum  safe  dose  is  1  Gm.  and  it  is 
seldom  that  a  total  dose  of  more  than  10  Gm.  in 
24  hours  is  employed.  In  acute  rheumatic  fever, 
300  mg.  to  1.3  Gm.  (approximately  5  to  20  grains) 
may  be  given  every  hour  until  a  daily  total  of 
about  10  Gm.  has  been  given.  Children  tolerate 
proportionately  larger  doses.  Sodium  bicarbonate 
is  often  administered  in  equal  amount  with  each 
dose  to  lessen  gastric  irritation. 

Storage. — Preserve  "in  well-closed  contain- 
ers." U.S.P. 

ACETYLSALICYLIC  ACID 
CAPSULES.  N.F. 

Aspirin  Capsules 

"Acetylsalicylic  Acid  Capsules  contain  not  less 
than  93  per  cent  and  not  more  than  107  per  cent 
of  the  labeled  amount  of  C9H8O4."  N.F. 

Usual  Size. — 5  gr.  (approximately  300  mg.). 

ACETYLSALICYLIC   ACID  TABLETS 

U.S.P.  (B.P.,  LP.) 

Aspirin  Tablets  [Tabellae  Acidi  Acetylsalicylici] 

"Acetylsalicylic  Acid  Tablets  contain  not  less 
than  95  per  cent  and  not  more  than  105  per  cent 
of  the  labeled  amount  of  C9H804."  U.S.P.  The 
corresponding  B.P.  limits  are  94.5  per  cent  and 
105.0  per  cent;  the  LP.  limits  are  the  same  as 
those  of  the  U.S.P. 

B.P.  Tablets  of  Acetylsalicylic  Acid.  LP.  Compressi 
Acidi  Acetylsalicylici.  Sp.  Tabletas  de  Acido  Acetilsalicilico. 

Assay. — A  representative  sample  of  tablets, 
equivalent  to  about  500  mg.  of  acetylsalicylic 
acid,  is  mixed  with  neutralized  alcohol,  cooled  to 
from  15°  to  20°,  and  titrated  with  0.1  N  sodium 
hydroxide  T.S.,  using  phenolphthalein  T.S.  as  in- 
dicator. In  this  titration  the  carboxyl  group  of 
acetylsalicylic  acid  is  neutralized,  as  well  as  any 
acetic  and  salicylic  acids  that  may  be  present.  To 
the  mixture  is  added  a  volume  of  0.1  N  sodium 
hydroxide  equal  to  that  used  in  the  titration,  plus 
15  ml.  more;  the  mixture  is  heated  in  a  boiling 


water  bath  for  15  minutes  to  convert  the  sodium 
acetylsalicylate  to  sodium  acetate  and  sodium 
salicylate.  After  cooling  the  mixture  to  room  tem- 
perature the  excess  of  alkali  is  titrated  with  0.1  iV 
sulfuric  acid,  using  phenolphthalein  T.S.  as  in- 
dicator. A  volume  of  0.1  N  sodium  hydroxide 
equal  to  that  added  the  second  time  is  then  mixed 
with  the  same  volume  of  alcohol  as  used  in  the 
test,  diluted  with  water  to  the  same  volume  and 
heated  for  the  same  period  of  time,  then  titrated 
with  0.1  N  sulfuric  acid.  Each  ml.  difference  in 
the  two  titration  figures  corresponds  to  18.02  mg. 
of  C9H.8O4,  U.S.P. 

The  B.P.  assay  is  essentially  the  same  as  the 
B.P.  employs  for  acetylsalicylic  acid.  The  validity 
of  the  assay  is  established  by  providing  a  limiting 
test  for  salicylic  acid. 

Usual  Sizes. — 1,  2%  and  5  grains  (approxi- 
mately 60,  150  and  300  mg.). 

ACETYLSALICYLIC  ACID,  ACETO- 
PHENETIDIN AND   CAFFEINE 
CAPSULES.     N.F. 

Aspirin,  Phenacetin,  and  Caffeine  Capsules; 
APC  Capsules 

"Acetylsalicylic  Acid,  Acetophenetidin  and  Caf- 
feine Capsules  contain  not  less  than  90  per  cent 
and  not  more  than  110  per  cent  of  the  labeled 
amounts  of  acetylsalicylic  acid  (C9H8O4),  aceto- 
phenetidin (C10H13NO2),  and  caffeine  (CsHio- 
N4O2."  N.F. 

Assay. — For  acetylsalicylic  acid. — A  chloro- 
form solution  containing  all  three  active  ingredi- 
ents is  shaken  with  a  sodium  bicarbonate  solution, 
which  removes  the  acetylsalicylic  acid.  Sodium 
hydroxide  is  added  to  the  aqueous  solution,  which 
is  heated  to  hydrolyze  the  acetylsalicylic  acid;  the 
resulting  salicylate  is  determined  by  reaction  with 
a  measured  excess  of  0.1  N  bromine,  in  the  pres- 
ence of  acid,  which  forms  tribromophenol  and 
carbon  dioxide.  Excess  bromine  is  estimated  by 
its  releasing  an  equivalent  amount  of  iodine,  which 
is  titrated  with  0.1  N  sodium  thiosulfate.  The 
equivalent  weight  of  acetylsalicylic  acid  in  this 
reaction  is  one-sixth  its  molecular  weight.  For 
acetophenetidin  and  caffeine. — The  chloroform 
solution  remaining  after  extraction  of  acetylsali- 
cylic acid  is  evaporated  to  dryness  and  the  residue 
of  acetophenetidin  and  caffeine  thus  obtained  is 
weighed.  The  residue  is  dissolved  in  a  small  vol- 
ume of  alcohol,  and  a  measured  volume  of  water 
is  added  to  precipitate  acetophenetidin,  which  is 
removed  by  filtration.  To  a  portion  of  the  filtrate 
a  measured  excess  of  0.1  N  iodine  is  added  to 
precipitate  the  caffeine;  this  precipitate  is  filtered 
off  and  the  excess  iodine  in  a  portion  of  the  fil- 
trate is  titrated  with  0.05  N  sodium  thiosulfate. 
The  equivalent  weight  of  caffeine  is  one-fourth 
its  molecular  weight,  based  on  the  formation  of 
C8H10N4O2.HI.I4.  The  weight  of  acetopheneti- 
din is  calculated  by  subtracting  the  weight  of 
caffeine  found  from  the  combined  weight  of 
acetophenetidin  and  caffeine.  N.F. 

Uses. — Combinations  of  acetylsalicylic  acid, 
acetophenetidin  and  caffeine  find  wide  usage  as 
analgetics.  It  would  appear  that  inclusion  of  caf- 
feine enhances  the  overall  analgetic  effect  in  clini- 
cal usage,  though  it  is  difficult  to  evaluate  the 


20  Acetylsalicylic   Acid,   Acetophenetidin    and    Caffeine   Capsules 


Part   I 


effect  quantitatively  and  it  is  not  apparent  what 
the  mechanism  may  be.  Some  clinicians  do  not 
believe  that  caffeine  contributes  to  the  efficacy 
of  the  preparation.  For  a  discussion  of  the  actions 
and  uses  of  the  component  drugs  see  the  respec- 
tive monographs  for  each. 

Storage. — Preserve  "in  well-closed  containers." 
N.F. 

ACETYLSALICYLIC  ACID,  ACETO- 
PHENETIDIN AND  CAFFEINE 
TABLETS.     N.F. 

Aspirin,  Phenacetin,  and  Caffeine  Tablets;  APC  Tablets 

"Acetylsalicylic  Acid,  Acetophenetidin  and  Caf- 
feine Tablets  contain  not  less  than  90  per  cent 
and  not  more  than  110  per  cent  of  the  labeled 
amounts  of  acetylsalicylic  acid  (CoHsO.*),  aceto- 
phenetidin (C10H13NO2),  and  caffeine  (CsHio- 
N4O2)."  N.F. 

For  assay  and  uses  see  the  preceding  mono- 
graph. 

Storage. — Preserve  "in  well-closed  containers." 
N.F. 

Usual  Size. — Tablets  containing  180  mg.  (ZYi 
grains)  of  acetylsalicylic  acid,  ISO  mg.  (2y2 
grains)  of  acetophenetidin,  and  30  mg.  (V2  grain) 
of  caffeine. 

TABLETS    OF    ACETYLSALICYLIC 
ACID  AND  PHENACETIN.     B.P. 

Tablets  of  Aspirin  and  Phenacetin,  Tabellae  Acidi 
Acetylsalicylici  et  Phenacetini 

The  B.P.  provides  a  formula  from  which  tab- 
lets, each  containing  226.8  mg.  (3j^  grains)  of 
acetylsalicylic  acid  and  162  mg.  {2Yi  grains)  of 
phenacetin,  may  be  prepared.  The  content  of 
acetylsalicylic  acid  is  required  to  be  within  the 
limits  of  94.5  to  105.0  per  cent  and  that  of  phe- 
nacetin within  the  limits  of  95.0  to  105.0  per  cent 
of  the  amounts  specified,  respectively,  by  the 
formula. 

Tests  and  Assay. — The  presence  of  acetyl- 
salicylic acid  is  confirmed  by  chemical  identifica- 
tion tests,  while  that  of  phenacetin  is  established 
by  specifying  that  the  melting  point  of  the  residue 
obtained  in  the  assay  for  phenacetin  shall  be 
about  134°. 

In  the  assay  for  acetylsalicylic  acid  a  repre- 
sentative sample  of  tablets  is  alkalinized  with 
sodium  hydroxide  solution  and  the  phenacetin  is 
extracted  with  chloroform,  which  solution  is  set 
aside.  The  acetylsalicylic  acid  in  the  aqueous 
solution  is  completely  hydrolyzed  by  heating  the 
alkaline  solution  and  the  resulting  salicylic  acid 
determined  by  adding  an  excess  of  0.1  N  bromine, 
which  forms  tribromophenol  and  carbon  dioxide; 
the  excess  of  bromine  is  measured  through  release 
of  an  equivalent  amount  of  iodine,  which  is 
titrated  with  0.1  TV  sodium  thiosulfate.  The 
equivalent  weight  of  acetylsalicylic  acid  in  this 
assay  is  one-sixth  of  its  molecular  weight,  since 
three  molecules  of  bromine  react  with  a  molecule 
of  salicylic  acid.  To  assay  for  phenacetin  the 
chloroform  solution  set  aside  in  the  preceding 
assay  is  evaporated  to  dryness  and  the  residue 
of  acetophenetidin  weighed  after  drying  at  105°. 
B.P. 


This  is  a  popular  analgesic  combination  for 
which  the  B.P.  gives  the  dose  as  1  or  2  tablets. 

TABLETS    OF    ACETYLSALICYLIC 

ACID   WITH    IPECACUANHA 

AND  OPIUM.     B.P. 

Tablets  of  Aspirin  and  Dover's  Powder,  Tabellae  Acidi 
Acetylsalicylici  cum  Ipecacuanha  et  Opio 

The  B.P.  provides  a  formula  from  which  tab- 
lets, each  containing  162  mg.  {2]/2  grains)  of 
acetylsalicylic  acid  and  162  mg.  (2y2  grains)  of 
Powder  of  Ipecacuanha  and  Opium,  may  be 
prepared.  The  content  of  acetylsalicylic  acid  is 
required  to  be  within  the  limits  of  94.5  to  105.0 
per  cent  of  the  amount  of  that  substance  speci- 
fied, and  that  of  anhydrous  morphine,  C17H19- 
NO3,  within  the  limits  of  0.90  to  1.10  per  cent 
of  the  amount  of  powder  of  ipecacuanha  and 
opium  specified  by  the  formula. 

Tests  and  Assay. — Identification  tests  for 
the  several  constituents  are  provided.  In  the 
assay  for  acetylsalicylic  acid  a  representative 
portion  of  the  powdered  tablets  is  heated  with 
dilute  sulfuric  acid,  which  effects  hydrolysis  of 
the  aspirin  to  acetic  and  salicylic  acids.  The  latter 
is  extracted  with  ether,  which  is  then  extracted 
with  a  sodium  hydroxide  solution,  and  the  sali- 
cylic acid  finally  determined  as  explained  in  the 
assay  for  Tablets  of  Acetylsalicylic  Acid  and 
Phenacetin.  An  assay  for  morphine  is  performed 
by  the  method  employed  in  the  assay  for  Powder 
of  Ipecacuanha  and  Opium.  B.P. 

This  combination  is  employed  as  an  anti- 
pyretic in  the  treatment  of  acute  febrile  condi- 
tions; the  dose  is  1  or  2  tablets. 

ACONITE.    N.F.  (LP.) 

Aconite  Root,  Monkshood,  Aconiti  tuber,  [Aconitum] 

"Aconite  is  the  dried  tuberous  root  of  Acotiitum 
Napellus  Linne  (Fam.  Ranunadacece) .  The  po- 
tency of  Aconite  is  such  that  100  mg.  possesses 
an  activity  equivalent  to  not  less  than  150  meg. 
of  Reference  Aconitine."  N.F.  The  LP.  requires 
Aconite  Root  to  contain  not  less  than  0.6  per  cent 
of  the  alkaloids  of  aconite,  of  which  not  less  than 
30  per  cent  consists  of  aconitine. 

LP.  Aconiti  Tuber;  Aconite  Root.  Wolfsbane;  Friar's 
Cap;  Blue  Rocket.  Aconiti  Tuber;  Tubera  Aconiti;  Radix 
Aconiti.  Fr.  Aconit  napel ;  Coqueluchon.  Ger.  Eisenhut- 
knollen;  Aconitknollen;  Fuchswurz;  Monchswurz;  Wolfs- 
wurzel.  It.  Aconito.  Sp.  Tuberculo  de  aconito;  Raiz  de 
aconito. 

The  name  Aconite  is  derived,  according  to 
Pliny,  from  the  ancient  Black  Sea  port,  Aconis. 
Some  species  of  aconite  was  used  by  the  ancient 
Chinese  as  well  as  by  the  hill  tribes  of  India. 
While  the  physicians  of  Myddvai  indicated  the 
importance  of  aconite  as  a  remedy  during  the  13th 
century,  it  was  introduced  into  modern  medicine 
by  Storck,  of  Vienna,  in  1763.  The  drug  was  ad- 
mitted into  the  London  Pharmacopoeia  in  1788 
and  into  the  first  U.S. P.  The  genus  Aconitum  is 
a  relatively  large  one.  there  being  some  sixty  well- 
defined  species,  nearly  half  of  which  have  been 
used  in  medicine.  The  species  which  is  official  and 
recognized  by  nearly  all  the  pharmacopoeias  is 
Aconitum  Napellus.  It  is  indigenous  to  the  moun- 
tainous regions  of  Middle  Europe  and  is  found 


Part  I 


Aconite 


21 


growing  in  the  Alps,  Pyrenees  and  mountainous 
districts  of  Germany,  Austria,  Denmark,  Sweden 
and  Siberia,  its  range  extending  eastward  to  the 
Himalayas.  It  is  not  found  in  India,  according  to 
Dutt,  the  nearest  approach  to  it  there  being 
A.  soongariciim  Stapf.  The  pure  species  occurs 
wild  in  North  America  as  an  escape  from  cultiva- 
tion. The  most  nearly  related  American  plant  is 
the  variety  delphinifolium  Ser.  which  occurs  from 
Alaska  to  British  Columbia.  Varieties  and  sub- 
species of  A.  Napellus  are  extensviely  cultivated 
in  temperate  climates  for  their  foliage  and  flowers. 
There  are  about  twenty  species  of  Aconitum 
which  are  indigenous  to  the  mountainous  regions 
of  the  United  States,  three  of  which  occur  in  the 
eastern  section,  the  remainder  being  distributed  in 
the  west,  chiefly  in  the  Rocky  Mountains. 

Aconitum  Napellus  is  a  perennial  herb  attain- 
ing a  height  of  0.7  to  1.5  meters,  with  a  fusiform 
to  conical  tuberous  root,  seldom  exceeding  10  cm. 
in  length  and  2  cm.  in  thickness  near  the  summit, 
brownish  externally,  whitish  and  fleshy  within, 
and  sending  forth  numerous  long,  thick,  fleshy 
rootlets.  When  the  plant  is  in  full  growth,  there 
are  usually  two  or  three  roots  joined  together  by 
short  shoots  from  axillary  buds  at  the  base  of  the 
stem,  of  which  the  oldest  is  dark  brown,  fusi- 
form, wrinkled,  and  supports  the  stem,  while  the 
youngest  is  of  a  light  yellowish-brown  color  and 
conical  shape  and  is  destined  to  furnish  the  stem 
of  the  following  year,  the  old  root  decaying.  The 
stem  is  erect,  round,  smooth  and  leafy.  The 
leaves  are  alternate,  petiolate,  with  suborbicular, 
subcordate  to  broadly  ovate,  palmately  5-  to  7- 
parted  to  divided  blades,  from  two  to  four  inches 
in  diameter,  deep  green  upon  their  upper  surface, 
light  green  beneath,  somewhat  rigid,  and  more  or 
less  smooth  and  shining  on  both  sides.  Those  on 
the  lower  part  of  the  stem  have  long  petioles  and 
five  or  seven  divisions;  the  upper,  short  petioles 
and  three  or  five  divisions.  The  divisions  are 
wedge-form,  with  two  or  three  lobes,  which  ex- 
tend nearly  or  quite  to  the  middle.  The  lobes  are 
cleft  or  toothed,  and  the  lacinice  or  teeth  are 
linear  or  linear-lanceolate  and  pointed.  The  flowers 
are  of  a  dark  violet-blue  color,  large  and  beauti- 
ful, and  are  borne  at  the  summit  of  the  stem 
upon  a  thick,  simple,  straight,  erect,  spike-like 
raceme,  beneath  which,  in  the  cultivated  plant, 
several  smaller  racemes  arise  from  the  axils  of 
the  upper  leaves.  There  are  2  lanceolate  bracts 
beneath  each  pediceled  flower.  The  sepals  are  five, 
the  upper  helmet-shaped  and  beaked,  nearly  hemi- 
spherical, open  or  closed,  the  two  lateral  roundish 
and  internally  hairy,  the  two  lower  oblong-oval. 
They  enclose  2  distinct,  hammer-like,  nectarif- 
erous petals  which  are  covered  by  the  hood  of 
the  posterior  sepal.  The  stamens  are  numerous 
and  hypogynous.  The  carpels  are  3  to  4  with 
bilobed  stigma. 

The  fruit  consists  of  3  to  4  beaked  follicles. 
The  seeds  are  angular,  wrinkled  and  very  acrid. 
They  rapidly  lose  their  germinating  power  upon 
drying  and  storing  and  are  for  the  greater  part 
non-viable  after  a  year. 

A  number  of  subspecies,  varieties  and  hybrids 
of  A.  Napellus  are  abundant  in  the  alpine  mead- 
ows and  mountain  forests  of  France,  Switzerland, 


and  Germany.  Many  of  these  are  cultivated  in 
the  gardens  of  Europe,  and  have  been  introduced 
into  this  country  as  ornamental  plants.  All  parts 
of  the  plants  are  acrid  and  poisonous.  The  leaves 
and  flowering  tops  (Aconiti  Folia)  were  formerly 
used  but  only  the  root  is  now  official.  The  fresh 
leaves  have  a  faint  narcotic  odor,  most  sensible 
when  they  are  rubbed.  Their  taste  is  at  first  bitter 
and  herbaceous,  afterward  burning  and  acrid, 
with  a  feeling  of  numbness  and  tingling,  on  the 
inside  of  the  lips,  tongue,  and  fauces,  which  is 
very  durable,  lasting  sometimes  many  hours.  The 
root  is  much  more  active  than  the  leaves;  an 
extract  from  the  latter  is  said  to  have  only  one- 
twentieth  of  the  strength  of  one  made  from  the 
former.  It  should  be  gathered  in  autumn  or  winter 
after  the  leaves  have  fallen,  and  is  not  perfect 
until  the  second  year.  It  has  been  mistakenly  sub- 
stituted for  horseradish  root,  as  a  condiment, 
with  fatal  effects.  The  studies  of  P.  W.  Squire 
seem  to  show  that  in  the  autumn  the  root  is  the 
most  active.  But  the  practical  difficulty  is  that  the 
root  of  A.  paniculatum  Lam.  cannot  be  distin- 
guished by  the  ordinary  collector  from  that  of 
A.  Napellus,  except  by  taste;  so  that  the  custom 
of  gathering  the  root  about  the  flowering  period 
is  probably  well  founded. 

Aconite  root  is  collected  chiefly  from  plants, 
representing  subspecies  and  varieties  of  A.  Napel- 
lus, growing  wild  in  the  cool  mountainous  re- 
gions of  Germany,  Hungary,  Switzerland,  Spain 
and  France.  The  tuberous  roots  are  dug  up  in 
autumn,  washed  and  carefully  dried.  The  total 
imports  of  this  drug  into  the  United  States  in 
1952  were  4470  pounds,  the  suppliers  being  Italy 
and  Spain. 

Commercial  aconite  root  shows  considerable 
variation  and  is  usually  a  mixture  of  six  or  seven 
different  kinds  of  tubers,  as  follows:  1.  Single 
fleshy  tubers  which  are  smooth,  light  brown  and 
full  of  starch.  2.  Single  tubers  which  are  single, 
somewhat  elongated  fusiform,  crowned  with  short 
stems,  dark  brown  and  longitudinally  furrowed. 
3.  Twin  or  triplet  tubers,  one  of  two  of  which 
(daughter  tuber  or  tubers)  being  bud-crowned 
and  the  other  (parent  tuber)  having  a  short  stem 
at  the  summit.  4.  Very  small  single  tubers  usually 
crowned  with  stems,  the  lower  portion  being  acute 
or  pointed.  5.  Single  tubers  which  are  almost  cyl- 
indrical, crowned  with  stems  and  either  fleshy  and 
nearly  smooth  or  more  or  less  shrunken  and  fur- 
rowed. 6.  Dark  brown  resinous  tubers.  7.  Frag- 
ments of  small  and  nearly  filiform  roots. 

The  root  has  a  feeble  earthy  odor.  Though 
sweetish  at  first,  it  has  afterward  the  same  effect 
as  the  leaves  upon  the  mouth  and  fauces.  It 
shrinks  much  in  drying,  and  becomes  darker,  but 
does  not  lose  its  acridity. 

Description. — "Unground  Aconite  occurs  as  a 
more  or  less  conical  root,  from  4  to  10  cm.  in 
length,  and  from  1  to  3.5  cm.  in  diameter  at  the 
crown;  externally  weak  brown  to  moderate  brown, 
smooth  or  longitudinally  wrinkled,  the  upper  end 
with  a  bud,  or  remains  of  bud-scales  and  stem- 
scar.  The  other  portions  possess  numerous  root- 
scars  or  short  rootlets.  The  fracture  is  short, 
horny,  or  somewhat  mealy;  and  the  internal  color 
is  yellowish  white  through  very  pale  orange  to 


22 


Aconite 


Part  I 


moderate  yellowish  brown.  The  bark  is  1  to  2  mm. 
in  thickness,  and  the  cambium  zone  is  usually 
5-  to  8-angled.  Aconite  has  a  very  slight  odor  and 
a  sweet  taste  soon  becoming  acrid  and  developing 
a  tingling  sensation,  followed  by  numbness." 
N.F.X.  For  histology  see  N.F.X. 

"Powdered  Aconite  is  pale  brown  to  weak  yel- 
lowish orange.  Starch  grains  are  numerous,  spheri- 
cal, somewhat  planoconvex,  single  or  2-  to  5-com- 
pound,  the  individual  grains  from  3  to  20  jx  in 
diameter  and  frequently  with  a  central  cleft; 
vessels  mostly  with  slit-like,  simple  pits,  some- 
times with  spiral  or  reticulate  thickenings  or  with 
bordered  pits;  stone  cells  single,  or  in  small 
groups,  tabular,  irregular,  rectangular,  or  elon- 
gated in  shape,  from  100  to  400  n  in  length,  walls 
strongly  lignified  and  having  simple  pores.  Also 
present  are  a  few  fragments  of  cells  with  brown- 
ish or  yellowish  walls;  numerous  fragments  of 
parenchyma,  the  cells  of  which  are  filled  with 
starch  grains.  Fibers  from  stems  are  few,  very 
long,  with  lignified  walls  and  marked  by  trans- 
verse or  oblique,  slit-like  pits."  N.F. 

Standards  and  Tests. — Aconite  contains  not 
more  than  5  per  cent  of  its  stems  and  not  more 
than  2  per  cent  of  foreign  organic  matter,  other 
than  stems.  N.F. 

Assay. — The  N.F.  directs  that  a  tincture  of 
the  drug  shall  be  prepared  and  assayed  as  directed 
under  Aconite  Tincture.  The  studies  of  Wolff e 
and  Munch,  described  under  Uses,  cast  doubt  on 
the  reliability  of  this  bioassay  as  an  evidence  of 
the  therapeutic  value.  Hoppe  and  Mollett  (/.  A. 
Ph.  A.,  1943,  32,  215),  investigating  the  assay 
technic  of  Rowe  in  which  white  mice  are  used 
instead  of  guinea  pigs,  reported  results  having  a 
standard  error  of  approximately  one  per  cent.  A 
biological  assay  method  for  aconite  tincture,  em- 
ploying intravenous  injections  in  mice  and  com- 
paring the  LD50  doses  of  a  reference  standard 
aconitine  solution  and  of  dilutions  of  the  tincture 
under  test,  has  been  developed  by  Barr  and 
Nelson  (/.  A.  Ph.  A.,  1949,  38,  518);  the  stand- 
ard error  of  a  series  of  assays  was  found  to  be 
less  than  2  per  cent.  A  method  based  on  the  mini- 
mum dose  necessary  to  produce  emesis  in  pigeons 
has  been  suggested  by  Christensen  and  Nelson 
(/.  A.  Ph.  A.,  1940,  29,  97). 

The  LP.  assay  for  total  alkaloids  specifies  ex- 
traction of  the  alkaloids  by  macerating  the  pow- 
dered drug  with  ether  in  the  presence  of  ammonia; 
an  aliquot  portion  of  the  ether  solution  is  evapo- 
rated to  dryness,  and  the  residue  titrated  with 
0.1  N  hydrochloric  acid  in  the  presence  of  methyl 
red  and  methylene  blue  as  a  mixed  indicator. 
Each  ml.  of  0.1  N  hydrochloric  acid  represents 
64.5  mg.  of  total  alkaloids,  calculated  as  aconitine. 
The  determination  of  the  proportion  of  aconitine 
is  based  on  the  residual  titration,  with  0.01  N 
sodium  hydroxide  and  0.01  N  hydrochloric  acid, 
of  the  benzoic  acid  obtained  from  this  alkaloid 
upon  alkaline  hydrolysis. 

A  chemical  assay  for  aconite  described  by 
Bronkhorst  (Pharm.  Weekblad,  1935,  72,  1056)  is 
based  on  hydrolysis  of  the  alkaloids  and  estima- 
tion of  the  liberated  acids.  The  method  distin- 
guishes aconitine,  benzoylaconine,  and  aconine. 
Baker  and  Jordan  (/.  A.  Ph.  A.,  1936,  25,  291) 


suggested  a  method  of  analysis  which  takes  ad- 
vantage of  the  difference  in  basic  dissociation 
constants  of  aconitine  and  benzoylaconine,  the 
latter  being  a  stronger  base.  Other  assay  methods 
have  been  suggested  by  Schulze  (Apoth.-Ztg., 
1933,  48,  94)  and  Neugebauer  {Pharm.  Zgt.,  1933, 
78,  1077). 

Constituents. — Aconitum  Napellus  contains 
several  alkaloids,  though  there  seems  to  be  some 
disagreement  as  to  their  identity. 

Aconitine  is  the  most  important  alkaloid  of  the 
official  drug.  First  isolated  by  Peschier  in  1820, 
apparently  in  an  impure  form,  it  was  first  obtained 
in  a  crystalline  state  by  Groves  in  1860.  There 
has  been  much  discussion  regarding  the  empirical 
formula  for  aconitine,  but  C34H47NO11  is  now 
generally  accepted;  it  is  acetylbenzoylaconine. 

The  alkaloid  melts  between  192°  and  196°  (with 
decomposition),  is  dextrorotatory,  crystallizes  in 
rhomic  prisms,  is  soluble  in  chloroform  and  in 
benzene,  less  soluble  in  ether  and  in  alcohol, 
and  almost  insoluble  in  water  and  in  petroleum 
ether.  It  forms  well-crystallized  salts  which  are 
laevorotatory. 

Aconitine  is  precipitated  from  its  solution  by 
caustic  alkalies,  but  not  by  ammonium  carbonate, 
nor  by  potassium  or  sodium  bicarbonate.  It  is 
easily  hydrolyzed  by  acids  or  alkalies.  In  general, 
it  has  the  incompatibilities  characteristic  of 
alkaloids. 

Many  facts  are  known  concerning  the  structure 
of  aconitine,  but  it  has  not  yet  been  fully  eluci- 
dated. The  molecule  contains  four  methoxyl 
groups,  three  hydroxyl  groups,  and  an  ethylimino 
group.  On  hydrolysis  by  water  under  pressure,  or 
by  boiling  with  dilute  acid,  a  molecule  of  acetic 
acid  and  one  of  benzoylaconine  are  produced; 
hydrolysis  by  alkalies  releases  both  acetic  and 
benzoic  acids  and  yields  aconine.  Outstanding 
contributions  to  knowledge  of  the  structure  of 
aconitine  have  been  made  by  Majima  (Ann. 
Chem.,  1936,  526,  116),  Freudenberg  (Ber.,  1937, 
70B,  349)  and  Suginome  (Ann.  Chem.,  1937,  533, 
172).  For  further  information  see  Henry's  Plant 
Alkaloids  (1949),  p.  674. 

Benzoylaconine,  also  known  as  benzaconine, 
isaconitine,  and  pier  aconitine,  accompanies  aconi- 
tine in  A.  Napellus.  Its  empirical  formula  is 
C32H45NO10,  and  it  is  formed  by  the  elimination 
of  the  acetyl  group  from  aconitine.  The  base  melts 
at  130°,  is  dextrorotatory,  but  forms  crystalline 
salts  which  are  levorotatory.  Its  toxicity  is  less 
than  that  of  aconitine  and  it  appears  to  differ 
somewhat  in  the  type,  as  well  as  in  the  degree,  of 
its  physiological  action. 

Aconine  results  from  the  hydrolysis  of  aconitine 
by  alkali,  but  also  occurs  naturally  in  A.  Napellus. 
It  represents  aconitine  deprived  of  its  acetyl  and 
benzoyl  groups,  and  has  the  formula  C25H41NO9. 
It  melts  at  132°,  is  dextrorotatory,  and  likewise 
yields  crystalline  salts  which  are  levorotatory. 
Aconine  behaves  as  a  cardiac  stimulant  and  is 
antagonistic  to  aconitine. 

The  alkaloid  neopelline,  C28H330s(OCH3)3- 
(NCH3).3H20,  was  isolated  by  Schulze  and 
Berger  (Arch.  Pharm.,  1924,  262,  553)  from  com- 
mercial "amorphous  aconitine."  It  is  amorphous; 
on   alkaline   hydrolysis  acetic   and   benzoic   acid 


Part  I 


Aconite 


23 


are  eliminated  and  neoline,  C23H39NO6,  is  formed. 
The  latter  base  is  given  the  formula  C24H11NO6 
by  Freudenberg  and  Rogers  (J.A.C.S.,  1937,  59, 
2572)  and  said  to  be  normally  present  in  A.  Napel- 
lus.  The  latter  authors  isolated  the  new  alkaloid 
napelline,  C22H33NO3,  and  found  sparteine  and 
/-ephedrine  in  amorphous  acontine  from  A.  Napel- 
lus.  For  an  informative  historical  review  on  the 
chemistry  of  aconite  see  the  article  by  Husa  in 
A.  Ph.  A.  Monograph  No.  1,  1938,  on  Aconite. 

Alkaloids  from  other  species  of  Aconite. 
— The  alkaloids  of  Aconitum  are  mainly  of  two 
kinds:  (1)  aconitines,  which  are  di-acyl  esters  of 
a  series  of  polyhydric,  amino-alcohols  (aconities) 
and  are  highly  toxic,  and  (2)  the  atisines,  which  are 
polyhydric  amino-alcohols  and  of  low  toxicity. 

Some  of  the  more  toxic  aconitines  include 
pseudaconitine,  from  A.  deinorrhizum  and  A.  Bal- 
fourii  (India) ;  japaconitine,  from  A.  uncinatum 
(Japan);  indaconitine,  from  A.  chasmanthum 
(India) ;  and  bikhaconitine,  from  A.  spicatum 
(India).  The  group  of  less  toxic  alkaloids  in- 
cludes atisine  from  A.  heterophyllum  and  palm- 
atisine  from  A.  palmatum.  For  a  complete  list  of 
aconite  alkaloids  and  their  distribution  among  the 
species,  see  Henry  {Plant  Alkaloids,  1949). 

Many,  probably  all,  species  of  aconite  contain 
one  or  more  alkaloids.  While  most  of  these  alka- 
loids are  poisonous,  there  is  not  sufficient  evidence 
that  their  physiological  action  is  the  same  as  that 
of  the  official  drug.  It  is  therefore  imperative 
that  none  of  the  other  species  be  employed  as  a 
substitute  for  the  official  aconite;  the  fact  that 
they  may  show  a  similar  degree  of  toxicity  on 
bio-assay  provides  no  assurance  of  similarity  of 
action,  for  the  method  of  assaying  aconite  gives 
no  indication  of  how  it  acts,  only  the  amount  re- 
quired to  kill. 

For  a  description  of  other  aconite  species  see 
U.S.D.,  24th  ed.,  p.  22. 

Uses. — Aconite  is  not  widely  used  in  the 
United  States.  The  pharmacologic  action  of  its 
chief  alkaloid,  aconitine,  is  stimulating  and  then 
depressing  on  the  central  and  peripheral  nervous 
system  and  resembles  that  of  protoveratrine  in 
some  respects.  On  the  cardiovascular  system  the 
action  suggests  that  of  quinidine.  Topically,  it  is 
a  counterirritant. 

History. — Aconite  was  well  known  to  the  an- 
cients as  a  powerful  poison;  it  appears  to  have 
been  used  as  an  arrow  poison  early  in  Chinese 
history  and  perhaps  also  by  the  inhabitants  of 
ancient  Gaul.  It  is  the  basis  of  the  legend  of  the 
"love  poison"  according  to  which  the  victim  could 
be  poisoned  by  sexual  contact  with  a  woman  who 
had  been  fed  aconite  daily  since  infancy  (Bull. 
Hist.  Med.,  1944,  15,  420).  Although  mentioned 
in  the  Meddygon  Myddfai,  published  in  Wales  in 
the  12th  century,  it  was  introduced  into  regular 
medicine  by  Baron  Storck  of  Vienna,  whose  ex- 
periments were  published  in  the  year  1762.  Geiger 
(Annaien  d.  Pharm.,  1834,  7,  269)  described 
aconitine. 

Action. — Locally  aconite  is  actively  irritant 
and  also  a  paralyzant  to  the  peripheral  sensory 
nerves.  When  applied  to  a  mucous  surface  it  pro- 
duces at  first  a  burning,  tingling  sensation  followed 
in  a  few  minutes  by  a  numbness.  This  sensation 


may  even  be  perceptible  after  the  systemic  in- 
gestion of  large  doses.  When  administered  inter- 
nally the  first  effect  is  generally  a  slowing  of  the 
pulse  due  to  stimulation  of  the  cardio-inhibitory 
centers,  with  consequent  fall  in  the  blood  pressure 
and  usually  some  slowing  of  respiration.  With 
large  doses,  in  the  lower  animals,  the  slow  pulse 
suddenly  becomes  irregular  and  rapid  with  further 
fall  of  the  blood  pressure.  These  irregularities 
are  apparently  due  to  excitation  of  heteropic  (mis- 
placed) impulses  in  the  heart  (Hueber  and  Lehr, 
Arch.  exp.  Path.  Pharm.,  1938,  189,  25).  The 
heart  becomes  more  and  more  irregular  and  even- 
tually passes  into  ventricular  fibrillation  (Tripod, 
Arch,  internat.  pharmacodyn.  therap.,  1951,  85, 
121),  which  is  antagonized  by  a-fagarine  or  pro- 
caine in  the  isolated  mammalian  heart.  According 
to  Hueber  and  Lehr,  magnesium  antagonizes  these 
cardiac  irregularities.  Aconite  increases  the  toxic 
effects  of  calcium  and  digitalis  on  the  heart. 

Wolffe  and  Munch  (/.  Pharmacol.,  1934,  51, 
471)  believe  that  the  cardiac  arrhythmia  is  due 
to  the  aconitine;  they  report  that  aconine  will 
slow  the  pulse  but  not  cause  irregularities.  There 
is  apparently  great  variability  in  the  potency  of 
aconite;  thus  Wolffe  (4.  Ph.  A.  Monograph  No.  1, 
1938)  gave  from  20  to  60  drops  of  an  official  tinc- 
ture to  a  number  of  patients  with  no  apparent 
effect.  Wolffe  and  Munch  believe  that  the  con- 
stituents of  aconite  that  are  not  toxic  to  guinea 
pigs  when  tested  by  the  official  assay — chiefly 
aconine — may  be  the  therapeutically  desirable 
substances.  Such  constituents  result  from  the 
hydrolysis  of  aconitine;  hence  such  a  preparation 
as  aconite  tincture  may  be  of  greater  value  when 
it  has  been  allowed  to  stand  long  enough  for  the 
aconitine  to  have  been  hydrolyzed,  which  effect, 
paradoxically,  is  accompanied  by  diminished  po- 
tency as  measured  by  the  guinea  pig  assay.  This 
may  account  for  the  reports,  from  many  practi- 
tioners, of  good  clinical  results  obtained  from  an 
old  aconite  preparation  which  had  decomposed  on 
standing. 

In  the  frog,  large  quantities  of  aconite  produce 
a  loss  of  reflex  activity,  which  is  apparently  due  to 
a  paralysis  of  sensation  as  voluntary  motion  is 
preserved  for  some  time  later,  although  it  too  may 
eventually  be  abolished.  The  drug  appears  to 
affect  both  the  sensory  nerves  and  the  receptive 
side  of  the  spinal  cord,  although  the  latter  is  in- 
volved comparatively  late  in  the  poisoning. 

Therapeutic  Use. — Aconite  was  formerly  used 
in  the  treatment  of  febrile  complaints ;  any  benefit 
it  may  have  exerted  is  attributable  to  the  lower- 
ing of  blood  pressure,  which  tends  to  promote 
sweating.  It  has  been  used  to  reduce  overaction 
of  the  heart,  especially  in  the  absence  of  organic 
lesions,  and  occasionally  to  reduce  high  blood 
pressure.  The  variability  of  its  potency  and  the 
closeness  of  its  therapeutic  and  toxic  closes  have 
been  responsible,  in  large  measure,  for  its  decline 
as  a  therapeutic  agent. 

Aconite  was  formerly  employed  for  its  local 
irritant  effect  and  anesthetic  action  in  peripheral 
neuralgias;  if  used  too  freely  for  this  purpose  it 
may  be  absorbed  through  the  skin  in  sufficient 
quantity  to  cause  serious  poisoning.  It  has  been 
employed  as  a  local  anesthetic  for  the  stomach  in 


24 


Aconite 


Part   I 


various  types  of  vomiting  or  gastralgia  but  be- 
cause of  its  systemic  effect  is  no  longer  thus  used. 

For  internal  use  the  tincture  (q. v.)  is  employed. 
As  a  febrifuge  this  was  formerly  given  in  a  dose 
of  0.12  ml.  every  10  minutes  for  an  hour,  then 
every  hour  until  the  fever  subsided.  For  external 
application  the  fluidextract  (N.F.  IX)  has  been 
employed  but  an  ointment  was  generally  pre- 
ferred. This  may  be  prepared  by  incorporating 
the  fluidextract  in  2  or  3  parts  of  lard  or  other 
base.  Aconite  and  Chloroform  Liniment,  official 
in  N.F.  VIII,  was  prepared  by  mixing  45  ml.  of 
aconite  fluidextract,  80  ml.  of  alcohol,  125  ml.  of 
chloroform,  and  750  ml.  of  camphor  and  soap 
liniment;  it  was  once  a  popular  counterirritant 
liniment.  The  U.S. P.  1870  recognized  a  plaster  of 
aconite.  S 

Toxicology. — Aconite  is  a  rapidly  acting  and 
powerful  poison  (Hartung,  J.A.M.A.,  1930,  95, 
1265).  The  symptoms  produced  by  an  overdose 
of  it  are  sensations  of  warmth  in  the  stomach, 
sometimes  with  nausea  but  usually  without  vomit- 
ing, slowing  of  the  pulse  and  of  the  respiration; 
the  skin  is  cool  and  moist,  and  there  is  profound 
prostration.  As  the  poisoning  progresses  the  res- 
pirations become  more  slow  and  shallow,  the  pulse 
becomes  increasingly  feeble,  and  toward  the  end 
rapid  or  very  irregular.  The  only  symptom  of 
diagnostic  importance  is  the  characteristic  numb- 
ness and  tingling  first  felt  in  the  lips  and  mouth, 
but  later  often  also  in  the  fingers.  At  times  there 
is  dimness  of  vision,  the  pupils  may  be  either  con- 
tracted or  dilated,  and  occasionally  delirium  and 
stupor  or  convulsions  may  precede  the  fatal 
termination.  Death,  from  cardio-respiratory  fail- 
ure, occurs  in  Yz  to  6  hours.  As  little  as  5  ml.  of 
the  tincture  may  cause  death.  Poisoning  has  re- 
sulted from  mistaking  aconite  for  other  plants, 
such  a  horse  radish. 

In  the  treatment  of  aconite  poisoning  the  pa- 
tient should  be  kept  absolutely  in  a  horizontal 
position,  or  with  the  feet  higher  than  the  head. 
If  respiration  is  depressed,  oxygen  is  indicated; 
artificial  respiration  may  be  needed.  Gastric  lavage 
is  preferable  to  emetics  as  the  latter  cause  strain 
upon  the  circulation.  Hatcher  (J.A.M.A.,  1935, 
105,  502)  recommended  potassium  permanganate 
as  a  chemical  antidote.  Hueber  and  Lehr  (loc. 
cit.)  and  Mladoveanu  (Arch,  internat.  pharm., 
1939,  63,  494)  suggested  parenteral  use  of  mag- 
nesium sulfate  to  antagonize  the  cardiac  effects 
in  aconite  poisoning.  Hartung  (Arch.  exp.  Path. 
Pharm.,  1912,  69,  176)  demonstrated  experi- 
mentally the  value  of  atropine.  Other  circulatory 
stimulants,  such  as  strychnine  or  ammonia,  may 
also  be  used.  Body  temperature  should  be  main- 
tained by  external  application  of  heat.  Bar- 
biturates may  be  used  to  control  convulsions. 

Dose,  of  aconite  root,  30  to  60  mg.  (approxi- 
mately y2  to  1  grain).  A  dose  of  150  mg.  in  24 
hours  should  seldom  be  exceeded. 

ACONITE  TINCTURE.     N.F.  (LP.) 

[Tinctura  Aconiti] 

"Aconite  Tincture  possesses  a  potency  per  ml. 
equivalent  to  150  meg.  of  Reference  Aconitine." 
N.F.  The  LP.  Tincture  of  Aconite  contains  0.045 


to  0.055  per  cent  w/v  of  total  alkaloids,  of  which 
not  less  than  30  per  cent  consists  of  aconitine. 

Tincture  of  Aconite  Root.  Fr.  Teinture  d'aconit  (racine). 
Ger.  Eisenhuttinktur.  It.  Tintura  di  aconito.  Sp.  Tintura 
de  aconito. 

Prepare  the  tincture  from  100  Gm.  of  aconite, 
in  fine  powder,  by  Process  P  as  modified  for 
assayed  tinctures  (see  under  Tinctures),  using  a 
menstruum  of  3  volumes  of  alcohol  and  1  volume 
of  water.  Macerate  the  drug  during  24  hours, 
then  percolate  at  a  rapid  rate.  Adjust  the  pH  of 
the  percolate  to  3  ±  0.2,  using  hydrochloric  acid; 
after  assaying  the  liquid,  dilute  it  to  the  required 
potency,  including  sufficient  acid  to  maintain  the 
specified  pH.  The  official  formula  produces  ap- 
proximately 1000  ml.  of  tincture.  N.F. 

The  adjustment  of  the  reaction  of  this  tincture 
is  based  on  the  finding  of  Swanson  and  Har- 
greaves  (/.  A.  Ph.  A.,  1927,  16,  296),  confirmed 
by  Haag  and  Hawkins  (J.  A.  Ph.  A.,  1930,  19, 
1284),  that  deterioration  of  the  tincture  (as  meas- 
ured by  the  official  assay — but  see  under  Uses  of 
Aconite)  is  in  large  measure  prevented  by  adjust- 
ing it  to  a  pH  of  2.5  to  3.0.  Hydrochloric  acid  was 
used  for  the  acidification. 

Assay. — Opinion  as  to  the  relative  merits  of 
chemical  and  biological  assay  of  aconite  is  di- 
vided, as  is  apparent  from  the  number  of  methods 
of  both  types  which  have  been  proposed,  some  of 
which  are  described  in  the  monograph  on  Aconite. 
The  N.F.  employs  a  biological  method  of  assay. 

The  first  of  the  biological  methods  to  have  been 
used  for  testing  aconite — in  fact  probably  the 
oldest  of  all  biological  methods  of  standardizing — 
was  that  suggested  by  Dr.  E.  R.  Squibb,  this  being 
based  upon  an  observation  of  the  characteristic 
effects  of  aconite  on  peripheral  sensory  nerve  end- 
ings. The  principle  of  the  method  consisted  in 
determining  the  lowest  dilution  in  which  a  given 
sample  taken  into  the  mouth  of  the  experimenter 
produced  the  first  perceptible  degree  of  tingling 
in  the  tongue.  The  method  was  carried  out  as  fol- 
lows :  After  rinsing  the  mouth  with  distilled  water, 
4  ml.  of  an  aqueous  solution,  representing  one 
part  of  aconite  root  to  600  parts  of  water,  was 
taken  into  the  anterior  part  of  the  mouth  and  held 
there  for  one  minute  and  then  expelled.  If  the 
drug  was  of  standard  quality  there  resulted  in  a 
few  minutes  a  characteristic  sensation,  too  slight 
to  properly  be  called  tingling  and  yet  closely  allied 
to  it.  If,  at  the  end  of  fifteen  minutes,  there  was 
no  distinct  sensation  the  drug  was  considered  to 
be  below  standard  and  stronger  solutions  were 
tested  in  the  same  manner.  On  the  other  hand,  if 
it  produced  a  sharp,  distinct  tingling  it  was 
stronger  than  normal  and  less  concentrated  solu- 
tions were  tested.  It  is  evident  that  personal  sus- 
ceptibility played  a  considerable  part  in  this 
method  and  it  was  necessary  for  the  experimenter 
to  standardize  himself  by  determining  his  sensi- 
tiveness toward  a  sample  of  known  potency. 
Even  then,  the  test  was  hardly  more  than  of 
qualitative  value. 

The  second  method,  adopted  as  the  N.F.  assay, 
is  based  on  a  comparison  of  the  toxicity  of  a 
known  dilution  of  the  tincture  with  a  standard 
solution  of  reference  aconitine.  Guinea  pigs  weigh- 


Part  I 


Acriflavine 


25 


ing  between  250  Gm.  and  350  Gm.,  but  not  dif- 
fering by  more  than  50  Gm.  in  weight  and  all 
from  the  same  colony  of  pigs,  are  used  in  the 
assay.  Injections  of  the  diluted  aconite  tincture, 
and  of  the  reference  aconitine  solution,  are  in- 
jected under  the  skin  of  the  abdomen  of  the  guinea 
pigs;  the  experiment  consists  in  determining  the 
dose  of  each  preparation  which  will  kill  not  more 
than  7  and  not  less  than  3  animals  of  groups  of  10 
animals  used  for  each  solution,  within  6  hours. 
When  the  respective  mortalities  from  the  refer- 
ence standard  and  the  preparation  being  assayed 
differ  by  not  more  than  2  animals  the  doses  may 
be  considered  equivalent  and  a  comparison  of 
relative  potencies  of  the  preparations  made.  The 
N.F.  states,  however,  that  "owing  to  many  vari- 
able factors  in  this  assay  which  make  it  difficult 
for  different  operators  to  obtain  identical  results, 
the  evidence  of  potency  within  20  per  cent  above 
or  20  per  cent  below  the  standard  is  accepted." 
For  other  methods  of  assay  see  under  Aconite. 

Alcohol  Content. — From  65  to  70  per  cent  by 
volume  of  C2H5OH.  N.F. 

There  was  formerly  employed  in  the  United 
States,  and  at  one  time  recognized  by  the  N.F., 
a  preparation  known  as  Fleming's  Tincture  of 
Aconite,  which  represented  70  per  cent  of  aco- 
nite root. 

Uses. — For  discussion  of  uses  of  aconite,  in- 
cluding the  tincture,  see  the  preceding  monograph. 
At  one  time  aconite  tincture  was  a  popular  prep- 
aration but  the  variation  in  its  potency  and  the 
uncertainty  of  its  action  have  materially  limited 
its  use. 

Dose,  0.3  to  1  ml.  (approximately  5  to  15 
minims). 

Storage. — Preserve  "in  tight,  light-resistant 
containers  and  avoid  exposure  to  direct  sunlight  or 
to  excessive  heat."  N.F. 


ACONITINE. 

Aconitinum 


LP. 


The  LP.  defines  aconitine  as  acetylbenzoylaco- 
nine,  and  requires  it  to  contain  not  less  than  99.0 
per  cent  of  C34H47NO11. 

Aconitine  is  usually  obtained  from  Aconitum 
Napellus.  In  one  of  the  several  extraction  proce- 
dures which  may  be  used  the  drug  is  exhausted 
with  methanol  containing  1  per  cent  of  tartaric 
acid.  The  extract  is  concentrated,  diluted  with 
several  volumes  of  water,  and  treated  with  pe- 
troleum ether  to  remove  fatty  impurities.  The 
aqueous  solution  is  then  alkalinized  with  ammonia 
and  the  total  alkaloids  extracted  with  ethyl  or 
isopropyl  ether,  or  with  benzene  or  toluene.  From 
this  solution  the  alkaloids  are  extracted  with  small 
volumes  of  36  per  cent  hydrobromic  acid;  on 
cooling  this  solution  aconitine  hydrobromide 
crystallizes,  particularly  if  some  ammonium  bro- 
mide is  added.  Instead  of  using  hydrobromic  acid, 
a  10  per  cent  solution  of  hydrochloric  acid  may 
be  used;  to  this  is  added  sodium  iodide  to  pre- 
cipitate the  aconitine  as  hydriodide. 

For  information  concerning  chemical  charac- 
teristics of  aconitine  see  Constituents,  under 
Aconite. 

Description. — Aconitine  occurs   in   colorless 


crystals  or  as  a  white,  crystalline  powder;  it  is 
odorless;  a  sensation  of  tingling,  free  from  bit- 
terness, is  produced  by  as  small  a  quantity  as 
6  micrograms  placed  on  the  tongue  (the  alkaloid 
is  extremely  poisonous!).  Aconitine  dissolves  in 
about  4500  parts  of  water,  in  about  40  parts  of 
ethanol  (90  per  cent),  in  about  70  parts  of  ether, 
in  about  2800  parts  of  petroleum  ether,  and  in 
about  10  parts  of  benzene;  it  is  very  soluble  in 
chloroform.  It  melts  between  192°and  196°,  with 
decomposition.  LP. 

Standards  and  Tests. — Identification. — An 
aqueous  solution,  made  slightly  acid  with  acetic 
acid,  yields  a  colorless,  well-crystallized  pre- 
cipitate upon  addition  of  potassium  iodide  T.S. 
Pseudoaconitine. — A  yellow  residue  is  produced 
on  moistening  aconitine  with  fuming  nitric  acid 
and  evaporating  to  dryness  on  a  water  bath;  on 
moistening  the  residue  with  a  freshly-prepared 
10  per  cent  (w/v)  solution  of  potassium  hydrox- 
ide in  alcohol  no  purple  color  is  produced.  LP. 

Assay.— About  300  mg.  of  aconitine  is  dis- 
solved in  10  ml.  of  0.1  N  hydrochloric  acid  and 
the  excess  acid  is  titrated  with  0.1  A7  sodium 
hydroxide,  using  methyl  red  as  indicator.  Each 
ml.  of  0.1  N  hydrochloric  acid  represents  64.6  mg. 
of  C34H47NO11.  LP. 

Uses. — While  aconitine  was  long  ago  deleted 
from  both  the  U.S. P.  and  the  B.P.  it  maintains  a 
degree  of  popularity  in  some  European  and  South 
American  countries  for  which  reason,  apparently, 
it  is  included  in  the  LP. 

In  neuralgia  aconitine  is  applied  externally  in 
the  form  of  a  2  per  cent  ointment;  the  alkaloid 
is  dissolved  in  8  parts  of  oleic  acid  and  this  solu- 
tion is  incorporated  in  an  ointment  base,  gener- 
ally lard.  A  2  per  cent  solution  of  aconitine  in 
oleic  acid  is  employed  for  the  same  purpose. 
Care  must  be  observed  in  applying  these  prepara- 
tions to  avoid  contact  with  mucous  membranes 
or  raw  skin. 

Aconitine  is  sometimes  given  internally  for  its 
diaphoretic  and  depressant  effect,  but  such  use 
may  be  dangerous  because  of  the  powerful  cardiac 
action  of  the  drug  (see  Uses,  under  Aconite). 

The  average  dose  of  aconitine  is  0.1  mg.  (ap- 
proximately %40  grain) ;  doses  up  to  0.3  mg.  (ap- 
proximately %oo  grain)  are  sometimes  given, 
which  in  very  rare  instances  have  been  cau- 
tiously increased  to  a  single  dose  of  1  mg.  (ap- 
proximately Vm  grain). 

Storage. — Preserve  in  a  well-closed  container, 
protected  from  light.  LP. 

ACRIFLAVINE.     N.F. 

Acriflavine  Base,  Neutral  Acriflavine,  [Acriflavina] 

"Acriflavine  is  a  mixture  of  3,6-diamino-10- 
methylacridinium  chloride  and  3,6-diaminoacri- 
dine  containing,  when  dried  at  105°  for  2  hours, 
not  less  than  13.3  per  cent  and  not  more  than  15.8 
per  cent  of  CI."  N.F. 

Trypaflavine  {Delta) ;  Gonacrine;  Neutroflavine;  Eufla- 
vine.  Acridinum  Hydrochloricum.  Fr.  Chlorhydrate  de 
diaminoacridine. 

Derivatives  of  acridine  have  long  been  em- 
ployed in  the  dye  industry,  "acridine  yellow" 
having  been  first  marketed  in  1889.  In  1896 
Tappeiner,  because  of  the  similarity  in  the  struc- 


26 


Acriflavine 


Part   I 


ture  of  acridine  and  quinoline,  made  some  experi- 
ments on  the  antimalarial  activity  of  acridine  de- 
rivatives, which,  however,  were  not  encouraging. 
It  was  not  until  1912  when  Benda  introduced 
diamino-acridinium-methyl-chloride,  which  Ehrlich 
(Ber.,  1913,  46,  1931)  showed  to  be  definitely 
trypanocidal,  that  acridine  dyes  became  of  medici- 
nal importance.  Since  then  a  number  of  com- 
pounds chemically  related  to  acriflavine  have  been 
used. 

Acriflavine  is  sometimes  called  acriflavine  base 
or  neutral  acriflavine  but  this  designation  is  hardlv 
correct,  for  Collins  (/.  A.  Ph.  A.,  1929,  17,  659) 
showed  that  in  aqueous  solution  the  pH  is  be- 
tween 3  and  5 ;  that  is,  it  is  distinctly  acid. 

The  preparation  of  acriflavine  involves  a  series 
of  reactions  which  may  be  summarized  as  fol- 
lows: Aniline  and  formaldehyde  undergo  inter- 
action to  form  4,4-diaminodiphenylmethane;  this 
is  nitrated  to  2,2'-dinitro-4,4'-diaminodiphenyl- 
methane  and  the  latter  is  reduced  with  tin  and 
hydrochloric  acid  to  form  the  stannichloride  of 
3,6-diaminoacridine;  after  acetylation  of  the 
amino  groups,  the  nitrogen  atom  in  the  ring  is 
methylated  by  the  use  of  methyl  ^-toluenesulfon- 
ate  and  the  acetyl  groups  are  subsequently  re- 
moved by  heating  with  hydrochloric  acid. 

The  preparation  of  pure  acriflavine  from  com- 
mercial samples  containing  much  diaminoacridine 
may  be  achieved  by  treatment  with  sodium  hy- 
droxide and  subsequent  recrystallization. 

Description. — "Acriflavine  occurs  as  a  deep 
orange,  odorless,  granular  powder.  Solutions  of 
Acriflavine  are  reddish  orange  in  color  and  become 
fluorescent  on  dilution.  One  Gm.  of  Acriflavine  dis- 
solves in  about  3  ml.  of  water.  It  is  incompletely 
soluble  in  alcohol,  is  nearly  insoluble  in  ether,  in 
chloroform,  and  in  fixed  oils."  N.F. 

Standards  and  Tests. — Identification. — (1) 
On  adding  a  few  drops  of  hydrochloric  acid  to  a 
solution  of  acriflavine  that  has  been  diluted  until 
it  just  exhibits  fluorescence  the  fluorescence  dis- 
appears but  reappears  partially  on  dilution  with 
distilled  water.  (2)  A  reddish-orange  crystalline 
precipitate  is  formed  on  adding  2  drops  of  sulfuric 
acid  to  1  ml.  of  a  1  in  250  aqueous  solution  of 
acriflavine.  (3)  No  effervescence  results  on  mix- 
ing equal  volumes  of  a  solution  of  acriflavine  with 
a  saturated  solution  of  sodium  bicarbonate  (acri- 
flavine hydrochloride  does  produce  an  efferves- 
cence). Loss  on  drying. — Not  more  than  8  per 
cent,  when  dried  for  2  hours  at  105°.  Residue  on 
ignition. — Not  over  35  mg.  from  1  Gm.  of  acri- 
flavine ignited  with  1  ml.  of  sulfuric  acid.  Water- 
insoluble  substances. — Not  over  0.5  per  cent. 
Arsenic. — 200  mg.  of  acriflavine  meets  the  re- 
quirements of  the  test  for  arsenic,  corresponding 
to  a  limit  of  10  parts  per  million.  N.F. 

Assay  for  Chlorine. — A  sample  of  about  250 
mg.  of  acriflavine,  previously  dried  for  2  hours 
at  105°,  is  dissolved  in  water  and  heated  with  a 
solution  containing  silver  nitrate,  sulfuric  acid 
and  potassium  permanganate  to  precipitate  silver 
chloride  while  oxidizing  the  remainder  of  the  acri- 
flavine molecule.  The  precipitate  is  filtered  on  a 
Gooch  crucible,  washed  first  with  1  in  3  nitric 
acid,  then  with  distilled  water,  and  dried  to  con- 


stant weight  at  105°.  Each  Gm.  of  silver  chloride 
represents  247.4  mg.  of  CI.  N.F. 

For  an  account  of  therapeutic  properties  see 
under  Acriflavine  Hydrochloride.  For  intravenous 
injection  the  "acriflavine  base"  is  preferable  to 
the  hydrochloride  because  of  its  lower  acidity. 
The  beginning  dose  which  has  been  used  is  about 
100  mg.  (approximately  \l/i  grains)  administered 
intravenously  once  a  day,  which  may  be  cautiously 
increased,  bearing  always  in  mind  the  possible 
injurious  effects  on  the  liver. 

Storage. — Preserve  "in  tight  containers."  N.F. 

ACRIFLAVINE  HYDROCHLORIDE. 

N.F. 

[Acriflavinae  Hydrochloridum] 

"Acriflavine  Hydrochloride  is  a  mixture  of  the 
hydrochlorides  of  3,6-diamino-10-methylacridin- 
ium  chloride  and  3,6-diaminoacridine,  yielding, 
when  dried  for  1  hour  at  105°,  not  less  than  23 
per  cent  and  not  more  than  24.5  per  cent  of  CI." 
N.F. 

Acid  Acriflavine;  Acid  Trypaflavine. 

The  two  NHs  groups  of  acriflavine  are  capable 
of  reacting  with  acids  to  form  salts;  thus,  acri- 
flavine may  form  a  monohydrochloride  and  a 
dihydrochloride.  The  official  substance  is  the 
monohydrochloride.  For  information  concerning 
the  chemistry  of  acriflavine  see  the  preceding 
monograph. 

Description. — "Acriflavine  Hydrochloride  oc- 
curs as  a  strong  reddish  brown,  odorless,  crystal- 
line powder.  Solutions  of  Acriflavine  Hydrochlo- 
ride are  dark  red  in  color  and  become  fluorescent 
on  dilution.  One  Gm.  of  Acriflavine  Hydrochlo- 
ride dissolves  in  about  3  ml.  of  water,  and  is 
soluble  in  alcohol.  It  is  nearly  insoluble  in  ether, 
in  chloroform,  in  liquid  petrolatum,  and  in  fixed 
or  volatile  oils.  One  Gm.  of  Acriflavine  Hydro- 
chloride, dissolved  in  50  ml.  of  warm  distilled 
water,  forms  a  clear  solution,  which  remains  clear 
and  free  from  sediment  on  standing  in  the  dark 
for  24  hours.  Dissolve  200  mg.  of  Acriflavine 
Hydrochloride  in  100  ml.  of  isotonic  sodium  chlo- 
ride solution:  a  clear  solution  is  obtained,  which 
remains  clear  and  free  from  sediment  on  standing 
in  the  dark  for  24  hours."  N.F.  The  solubility  of 
acriflavine  hydrochloride  varies  somewhat  with 
the  proportions  of  its  components,  hence  commer- 
cial samples  do  not  always  have  identical  solu- 
bilities. It  is  of  interest  that  the  mixture  is  more 
soluble  than  either  component. 

Standards  and  Tests. — Identification. — Acri- 
flavine hydrochloride  responds  to  the  tests  pre- 
scribed for  acriflavine  except  that  its  solutions  are 
dark  red,  and  in  test  (3)  an  effervescence  is  pro- 
duced. Loss  on  drying. — Not  over  7  per  cent  on 
drying  for  1  hour  at  105°.  Residue  on  ignition. — 
Not  over  10  mg.  from  1  Gm.  of  acriflavine  hydro- 
chloride with  1  ml.  of  sulfuric  acid.  Arsenic. — The 
requirement  is  the  same  as  for  acriflavine.  N.F. 

Assay. — The  N.F.  directs  that  the  assay  be 
performed  as  specified  under  Acriflavine. 

Incompatibilities. — Acriflavine  and  its  hydro- 
chloride are  incompatible  with  solutions  contain- 


Part  I 


Adrenal   Cortex  Injection  27 


ing  chlorine,  phenol  or  mercuric  chloride.  With 
alkalies  and  with  silver  nitrate  a  precipitate  is 
produced.  While  acriflavine  hydrochloride  is  com- 
patible with  normal  salt  solution  for  immediate 
use,  precipitation  occurs  upon  standing.  Salt  solu- 
tions stronger  than  5  per  cent  produce  a  pre- 
cipitate immediately.  Solutions  of  acriflavine 
hydrochloride  are  acid  and  may  give  rise  to  in- 
compatibilities for  this  reason. 

Uses. — The  most  important  use  of  acriflavine 
is  as  a  wound  antiseptic.  This  antiseptic  is  an  out- 
come of  investigations,  commencing  with  Ehrlich, 
to  find  a  dye  which  will  stain  the  microorganism, 
and  thereby  injure  it,  without  staining  the  tissues 
of  the  host;  thus  it  would  have  low  toxicity  to 
the  host.  In  addition  to  acriflavine,  the  related 
substances  aminacrine  hydrochloride  and  pro- 
flavine hemisulfate  are  official  in  the  B.P. 

Acriflavine  is  not  an  extremely  powerful  bac- 
tericide but  it  is  a  very  active  bacteriostatic  sub- 
stance. It  is  usually  employed  in  strengths  of 
about  1  in  1000  in  physiological  saline  solution. 
Browning,  who  advocated  use  of  acriflavine  as  a 
surface  antiseptic  in  1917,  reviewed  the  more  re- 
cent status  of  this  drug  (Brit.  M.  J.,  1943,  1,  341) 
as  follows:  it  is  bacteriostatic  against  important 
pyogenic  bacteria;  serum  does  not  diminish  its 
action  but  blood  and  pus  do ;  its  systemic  toxicity 
is  low  (100  mg.  intravenously  every  other  day 
for  10  doses  is  well  tolerated)  and  it  is  not  ab- 
sorbed sufficiently  from  wounds  to  be  toxic;  in 
the  1:1000  solution  concentration  it  causes  little 
tissue  damage;  phagocytosis  is  but  little  dis- 
turbed; skin  idiosyncrasy  is  rare;  it  is  able  to 
destroy  infection  in  a  fresh  wound  before  sig- 
nificant invasion  occurs;  established  infection  is 
cleaned  up  better  by  the  1 :1000  solution  than  by 
the  local  use  of  the  sulfonamide  drugs;  it  does 
not  delay  healing;  in  serum  a  concentration  of  1 
in  200,000  sterilizes  either  Staphylococcus  aureus 
or  Bacillus  coli  within  24  hours  and  is  active 
against  Streptococcus  pyogenes  in  even  higher  di- 
lutions; Bacillus  pyocyaneus,  proteus  and  some 
strains  of  coli  are  highly  resistant  to  acriflavine. 

Extensive  comparisons  of  the  bacteriostatic  and 
bactericidal  action  of  acriflavine  with  other  acri- 
dine  antiseptics  have  been  published  (/.  Pharma- 
col., 1944,  80,  217;  /.  Lab.  Clin.  Med.,  1944,  29, 
134  and  1177  and  1945,  30,  145).  Martin  and 
Fisher  (J.  Lab.  Clin.  Med.,  1944,  29,  383)  re- 
ported that  the  bacteriostatic  action  of  the  acri- 
dine  antiseptics  is  due  to  inhibition  of  adenine- 
containing  factors  such  as  coenzymes  I  and  II, 
which  are  essential  to  bacteria  (see  also  O'Connor, 
Brit.  J.  Exp.  Path.,  1951,  32,  547).  Garrod  (Brit. 
M.  /.,  April  4,  1931)  pointed  out  that  it  is  not  ad- 
visable to  apply  it  on  cotton  dressings  because  the 
affinity  for  cotton  reduces  its  antiseptic  action. 

Acriflavine  has  been  employed  as  an  injection 
in  gonorrheal  urethritis  in  1  in  1000  concentration 
and  as  a  bladder  irrigation  in  1  in  5000  concentra- 
tion. It  has  also  been  used  for  sterilizing  the  skin 
as  a  5  per  cent  solution  in  alcohol,  acetone  and 
water  (see  Tinker  and  Sutton,  J. A.M. A.,  1926, 
87,  1347  and  Berry,  Pharm.  J.,  1937,  139,  541, 
571).  Roxburgh  (Pract.,  1941,  146,  289)  advo- 
cated treatment  of  impetigo  by  removal  of  the 


crusts  and  painting  of  the  raw  area  with  1  in  1000 
acriflavine. 

Acriflavine  has  been  given  by  mouth  as  a  uri- 
nary antiseptic  in  doses  of  200  mg.  daily;  for  best 
effect  the  urine  must  be  kept  alkaline.  Assinder 
(Lancet,  1936,  1,  304)  reported  great  variation  in 
the  toxicity  of  different  samples. 

According  to  Crittenden  (/.  Pharmacol.,  1932, 
44,  423)  small  doses  cause  a  moderate  transient 
rise  in  blood  pressure,  while  large  doses  cause  a 
fall  in  blood  pressure  with  a  slowing  of  the  heart. 
He  also  found  considerable  difference  in  the 
toxicity  of  individual  samples.  Heathcoat  and 
Urquhart  (/.  Pharmacol.,  1930,  38,  145)  reported 
the  acutely  fatal  intravenous  dose  for  animals  as 
about  25  mg.  per  Kg.  but  that  repeated  injections 
of  less  than  half  of  this  quantity  eventually 
proved  fatal,  with  evidence  of  injurious  effects  on 
the  fiver  and  the  kidney  (see  also  Levrat,  Compt. 
rend.  soc.  biol.,  1933,  114,  60). 

Prior  to  the  availability  of  the  sulfonamides 
and  antibiotics,  a  2  per  cent  aqueous  solution  was 
used  intravenously  in  doses  of  10  to  15  ml.,  slowly, 
or  diluted  with  250  ml.  of  isotonic  sodium  chlo- 
ride solution,  at  intervals  of  1  or  3  days,  in  the 
treatment  of  brucellosis  (Debono,  Brit.  M.  J., 
199,  1,  326),  tularemia  (Loria,  Am.  J.  Med.  Sc, 
1941,  202,  803),  psittacosis  (Koch,  Deutsche 
med.  Wchnschr.,  1940,  32,  877),  blastomycosis 
(Pupo,  J.A.M.A.,  1928,  91,  1733),  trypanosomi- 
asis (Hawking,  Ann.  Prop.  Med.,  1938,  32,  367), 
leishmaniasis  (Senekji,  J.  Path.  Bact.,  1940,  50, 
171),  and  schistosomiasis  (Fisher,  Lancet,  1934, 
1,  897  and  2,  1017);  however,  Khali  and  Salah 
(Lancet,  1934,  2,  862)  reported  it  to  be  ineffec- 
tive in  the  last-named  condition,  [v] 

The  N.F.  states  that  acriflavine  and  its  hydro- 
chloride are  used  locally  in  1:1000  solution,  and 
for  irrigation  in  1:10,000  to  1:1000  solution.  For 
intravenous  dosage  see  under  Acriflavine. 

To  remove  stains  of  acriflavine  or  its  hydro- 
chloride from  the  hands  it  is  recommended  that  a 
little  dilute  sulfurous  acid  be  applied,  followed  by 
dilute  hydrochloric  acid,  then  washed  with  water. 

Storage. — Preserve  "in  tight  containers."  N.F. 

ADRENAL  CORTEX  INJECTION. 
U.S.P. 

"Adrenal  Cortex  Injection  is  a  sterile  solution 
in  alcohol  and  water  for  injection  containing  a 
mixture  of  the  endocrine  principles  derived  from 
the  cortex  of  adrenal  glands  of  healthy  domestic 
animals  used  for  food  by  man.  Each  ml.  of  Ad- 
renal Cortex  Injection  exhibits  a  biological  activity 
equivalent  to  that  of  100  micrograms  of  U.S.P. 
Hydrocortisone  Acetate  Reference  Standard.  It 
contains  a  suitable  antibacterial  agent."  U.S.P. 

The  adrenal  glands,  also  known  as  suprarenal 
glands  and  suprarenal  bodies  and  suprarenal  cap- 
sules, are  small  glandular  bodies  found  in  all 
mammals,  being  located  immediately  above  the 
kidney.  In  man  they  weigh  about  6  or  7  Gm.  They 
consist  of  two  distinct  portions:  an  outer  layer, 
known  as  the  cortex,  varying  in  thickness  from 
0.25  to  1.2  mm.,  and  an  inner,  medullary  portion. 
It  has  long  been  recognized  that  extirpation  of 


28  Adrenal   Cortex   Injection 


Part  I 


these  glands  in  lower  animals  is  almost  invariably 
fatal  within  a  week  or  two. 

The  physiologically  important  principle  of  the 
medullary  portion  of  adrenal  glands  is  epinephrine 
(for  information  see  under  Epinephrine),  while 
the  cortex  contains  a  large  number  of  compounds, 
several  of  which  have  pronounced  physiological 
activity.  Fractionation  of  pure  extracts  of  adrenal 
cortex  (about  9  Gm.  of  extract  is  obtained  from 
1000  pounds  of  adrenal  glands)  by  Kendall, 
Reichstein,  Wintersteiner,  Kuizenga,  Cartland 
and  others  has  led  to  the  isolation  of  28  crystalline 
steroids  and  a  residual  amorphous  fraction  from 
which  latter  there  was  recently  isolated  still  an- 
other crystalline  steroid.  At  least  seven  of  the 
crystalline  compounds  (including  the  one  most 
recently  isolated)  have  activity  which  is  charac- 
teristic of  the  adrenal  cortex.  Several  androgens 
and  estrogens  are  included  in  the  group  of  hor- 
mones which  have  been  isolated  but  since  their 
activity  is  not  specific  for  the  adrenal  gland  they 
are  not  of  primary  interest  in  any  discussion  of 
characteristic  adrenal  cortex  hormones.  The  seven 
hormones  of  interest  in  this  connection  are:  11- 
desoxycorticosterone,  the  one  which  possesses  the 
greatest  activity  in  maintaining  life  in  adrenalec- 
tomized animals,  official  in  the  U.S. P.  as  Desoxy- 
corticosterone  Acetate;  11-dehydrocorticosterone, 
known  also  as  Kendall's  Compound  A;  corticos- 
terone,  known  also  as  Kendall's  Compound  B  and 
Reichstein's  Substance  H;  17-hydroxy-l  1-dehy- 
drocorticosterone,  known  also  as  Kendall's  Com- 
pound E,  Wintersteiner' s  Compound  F  and  Reich- 
stein's Substance  Fa,  and  official  in  the  U.S. P.  as 
the  acetate  under  the  title  Cortisone  Acetate;  17- 
hydroxycorticosterone,  known  also  as  Kendall's 
Compound  F  and  Reichstein's  Substance  M,  and 
official  in  the  U.S. P.  as  Hydrocortisone  and  also, 
in  the  form  of  the  acetate,  as  Hydrocortisone 
Acetate;  17  -  hydroxy  - 11  -  desoxycorticosterone, 
known  also  as  Reichstein's  Substance  S;  the  new 
crystalline  hormone,  with  high  activity  in  the 
control  of  mineral  metabolism,  first  called  elec- 
trocortin  but  renamed  aldosterone  after  its  chem- 
ical structure  was  established  to  be  llP,21-dihy- 
droxy-3,20-diketo-4-pregnene-18-al  (for  details  of 
isolation  and  characterization  see  Harman  et  al., 
J.A.C.S.,  1954,  76,  5035;  for  other  information 
see  under  Desoxycorticosterone  Acetate). 

For  a  summary  of  the  procedure  for  preparing 
active  extracts  of  the  adrenal  cortex,  and  for  their 
fractionation,  as  well  as  the  chemistry  of  the  in- 
dividual compounds,  see  Kuizenga  in  the  A.A.A.S. 
volume  on  The  Chemistry  and  Physiology  of 
Hormones  (1944).  Manufacturing  details  may  be 
found  also  in  U.  S.  Patents  2,053,549  (1936)  and 
2,096.342  (1937). 

Under  the  title  Suprarenal  the  dried,  partially 
defatted  and  powdered  suprarenal  gland  of  cattle, 
sheep,  or  swine,  representing  approximately  6 
parts  by  weight  of  fresh  glands,  was  long  offi- 
cially recognized,  most  recently  in  N.F.  VIII.  For 
information  concerning  it  see  U.S.D.,  24th  ed., 
p.  1171. 

Description. — "Adrenal  Cortex  Injection  is 
a  clear,  colorless,  or  faintly  colored  solution." 
U.S.P. 

Standards  and  Tests.— pH—  The  pH  of  the 


injection  is  between  4.0  and  6.0.  Pyrogen. — The 
injection  meets  the  requirements  of  the  official 
pyrogen  test,  the  test  dose  being  1  ml.  per  Kg. 
Other  requirements. — The  injection  meets  the  re- 
quirements for  Injections.  Pressor  substances. — 
The  injection  exhibits  a  pressor  activity  equivalent 
to  not  more  than  0.2  mg.  of  epinephrine  in  each 
100  ml.  U.S.P. 

Assay. — The  assay  is  based  on  measurement  of 
the  ability  of  the  adrenal  cortex  injection  under 
test  to  promote  deposition  of  glycogen  in  the  liver 
of  adrenalectomized  rats;  in  the  assay  the  liver 
glycogen  content  is  determined  through  interac- 
tion of  glucose  obtained  from  the  glycogen  with 
alkaline  cupric  sulfate  T.S.,  followed  by  estima- 
tion of  the  excess  of  cupric  ion  by  release  of 
iodine  and  titration  with  sodium  thiosulfate  volu- 
metric solution.  Quantitative  evaluation  of  the 
effect  is  obtained  by  comparison  with  the  effect 
produced  by  Hydrocortisone  Acetate  Reference 
Standard  under  similar  experimental  conditions. 
U.S.P. 

Uses. — The  chief  indication  for  suprarenal  ex- 
tract is  in  the  management  of  acute  crises  in 
Addison's  disease;  maintenance  therapy  is  simpler, 
more  effective,  and  less  costly  when  cortisone  or 
hydrocortisone,  desoxycorticosterone  and  sodium 
chloride  are  used.  Since  the  adrenal  extract  is 
more  efficient  in  the  muscle  work  test  than  any 
combination  of  isolated  adrenal  steroids  it  is  pos- 
sible that  it  contains  unidentified  factors  which 
may  have  therapeutic  value  in  various  conditions. 
On  the  other  hand  Thorn  et  al.  (New  Eng.  J. 
Med.,  1953,  248,  420)  found  that  intravenous 
injections  of  hydrocortisone  produce  rapid  meta- 
bolic effects  of  maximal  intensity  and  believe  that 
this  dosage  form  will  eventually  replace  adrenal 
extract  for  use  in  the  correction  of  acute  adrenal 
insufficiency.  The  characteristics  and  treatment  of 
adrenal  insufficiency  are  discussed  under  Desoxy- 
corticosterone Acetate,  while  hyperfunction  of 
the  adrenal  gland  is  discussed  under  Cortisone 
Acetate. 

History. — Thomas  Addison  described,  in  1855, 
the  syndrome  of  adrenal  insufficiency  which  is 
commonly  referred  to  as  Addison's  disease.  In 
1856  Brown-Sequard  reported  his  experimental 
demonstration,  in  animals,  that  the  adrenal  gland 
is  essential  for  life.  Osier's  report  (Internat.  Med. 
Mag.,  1896,  5,  3)  that  oral  administration  of  a 
glycerin  extract  of  fresh  hog  adrenal  glands  pro- 
duced marked  improvement  in  a  patient  with 
Addison's  disease  was  obscured  and  forgotten 
when  the  vasopressor  action  of  adrenal  extracts 
was  recognized  by  Oliver  and  Schafer  in  1895 
(see  Brit.  M.  J.,  1901,  1,  1009)  and  by  the  failure 
of  epinephrine  to  improve  the  patient  with  adre- 
nal insufficiency.  That  it  is  the  cortex  of  the 
adrenal  gland  which  is  essential  for  life  was  dem- 
onstrated by  Houssay  and  Lewis  (Am.  J.  Physiol., 
1923,  66,  512)  and  others.  About  three  decades 
after  Osier's  report.  Hartman  et  al.  (Proc.  S.  Exp. 
Biol.  Med.,  1927,  25,  69),  and  Rogoff  and  Stewart 
(Science,  1927,  66,  327)  reported  prolongation  of 
life  in  adrenalectomized  animals  following  admin- 
istration of  an  extract  of  the  adrenal  cortex. 
Swingle  and  Pfiffner  (ibid.,  1930,  71,  321)  pre- 
pared a  potent  extract  which  proved  to  be  clini- 


Part  I 


Adrenal   Cortex   Injection  29 


cally  effective  (see  Rowntree,  J. A.M. A.,  1940, 
114,  2526)  and  which  came  into  use  under  the 
name  Eschatin  (Parke,  Davis);  Hartman  and 
Brownell  (Proc.  S.  Exp.  Biol.  Med.,  1930,  27, 
938)  simultaneously  produced  a  potent  extract 
which  was  also  useful  in  patients.  In  the  light  of 
later  knowledge  of  the  activity  of  adrenal  cortical 
steroids,  these  extracts  were  weak,  costly,  and 
available  in  insufficient  quatnity  for  many  thera- 
peutic requirements.  Improved  extraction  meth- 
ods were  reported  by  Kuizenga  et  al.  (J.  Biol. 
Chem.,  1943,  147,  561).  Currently  available  ex- 
tracts are  standardized  on  adrenalectomized  rats 
to  have  a  liver  glycogen  deposition  activity  cor- 
responding to  that  of  0.1  mg.  of  hydrocortisone 
acetate  per  ml.  (see  U.S. P.  requirement  and  assay 
above j.  Extracts  have  also  been  standardized  using 
adrenalectomized  dogs  (Cartland  and  Kuizenga, 
Am.  J.  Physiol.,  1936,  117,  678);  a  dog  unit  is 
the  amount  of  material  per  Kg.  of  body  weight 
required  daily  to  maintain  the  animal  in  good 
condition  with  a  normal  blood  non-protein  nitro- 
gen level.  Dog  units  may  be  transposed  in  terms 
of  hydrocortisone  on  the  assumption  that  50  dog 
units  are  equivalent  to  0.1  mg.  of  hydrocortisone. 
The  most  active  extract  developed,  Lipo-Adrenal 
Cortex,  Sterile  Solution  (Upjohn),  contains  in  1 
ml.  the  activity  of  1  mg.  of  hydrocortisone. 

Action. — Physiologically,  the  adrenal  cortex 
hormones,  which  are  present  in  extracts,  fall  into 
two  categories:  11-desoxycorticosterone,  17-hy- 
droxy-11-desoxycorticosterone  and,  apparently, 
aldosterone  (electrocortin)  are  concerned  chiefly 
with  electrolyte  and  fluid  balance;  corticosterone, 
1 1-dehydrocorticosterone,  1 7-hydroxycorticoster- 
one  (hydrocortisone),  and  17-hydroxy-l  1-dehy- 
drocorticosterone (cortisone)  are  more  active  in 
carbohydrate  and  protein  metabolism.  The  loss  of 
sodium  seems  to  be  related  to  the  inability  of 
renal  tubules  to  reabsorb  sodium;  this  is  perhaps 
the  most  serious  defect  in  adrenal  insufficiency 
and  is  corrected  by  adrenal  cortical  extracts 
(Thorn  et  al.,  Endocrinology,  1937,  21,  213). 
The  hormones  of  the  second  category,  which  have 
an  oxygen  or  a  hydroxyl  group  in  the  11  position, 
seem  to  increase  conversion  of  protein  to  carbo- 
hydrate (gluconeogenesis)  and  utilization  of  car- 
bohydrate in  the  liver  but  to  decrease  peripheral 
utilization  of  glucose  (Long,  ibid.,  1942,  30,  870); 
this  antagonizes  the  action  of  insulin  which  tends 
to  promote  protein  synthesis  and  increase  periph- 
eral utilization  of  carbohydrate.  Adrenal  cortex 
extracts  correct  the  abnormality  in  carbohydrate 
metabolism  (Hartman  et  al.,  J.A.M.A.,  1932,  98, 
788).  The  decreased  ability  of  muscles  to  work  is 
perhaps  related  to  this  defect  in  protein  and  car- 
bohydrate metabolism  (Lewis  et  al.,  Endocrinol- 
ogy, 1940,  27,  971;  Ingle,  ibid.,  1942,  31,  419) 
but  these  metabolic  effects  are  inadequately  under- 
stood and  a  complex  interaction  of  pituitary, 
thyroid,  pancreas  and  other  organs  is  probably 
involved.  Adrenal  hormones  also  maintain  normal 
capillary  permeability.  The  bronze  pigmentation 
of  the  skin  of  the  patient  with  Addison's  disease 
becomes  lighter  when  adrenal  cortex  extract  is 
employed  (Hartman  et  al,  J.A.M.A.,  1932,  99, 
1478).  Resistance  to  infection  and  stress  of  all 
types  is  related  to  adrenal  function.  Increase  in 


blood  lymphocytes  (White  and  Dougherty,  Endo- 
crinology, 1945,  36,  207)  and  decrease  in  serum 
gamma  globulin  content  (immune  bodies)  in  defi- 
ciency states  are  corrected  by  the  steroid  hor- 
mones. 

For  therapeutic  purposes  both  groups  of  adre- 
nal steroid  hormones  are  needed,  and  are  provided 
by  the  available  extracts.  However,  very  large 
doses  are  necessary,  and  the  cost  is  sometimes 
prohibitive.  The  less  costly  synthetic  compound 
desoxycorticosterone  acetate  has  made  it  possible 
to  control  the  disturbance  in  water  and  electrolyte 
metabolism,  though  this  compound  does  not  pre- 
vent hypoglycemia,  particularly  in  association 
with  infections,  gastrointestinal  disturbances  or 
other  states  of  stress.  The  present  availability  of 
cortisone  and  hydrocortisone  provides  an  ample 
supply  of  glycocorticoid  activity. 

Therapeutic  Uses. — The  management  of 
adrenal  insufficiency,  as  presented  by  Thorn 
(J.A.M.A.,  1944,  125,  10)  involves  several  fac- 
tors (see  also  under  Desoxycorticosterone  Ace- 
tate, Cortisone  Acetate,  and  Hydrocortisone  Ace- 
tate). In  the  acute  crisis,  bed  rest  is  essential. 
Water  and  salt  are  greatly  needed,  and  up  to  4 
liters  of  isotonic  sodium  chloride  solution  should 
be  given  intravenously  during  the  first  24  hours. 
Dextrose  is  also  needed,  being  given  intravenously 
in  5  per  cent  solution  in  water  for  injection  or 
isotonic  sodium  chloride  solution  but  it  must  be 
administered  with  caution  because  fatalities  have 
resulted  from  rapid  and  unintelligent  administra- 
tion. Adrenal  cortex  extract  is  started  at  once  in 
a  dose  of  30  to  50  ml.  intravenously  and,  simul- 
taneously, 10  ml.  intramuscularly;  the  latter  is 
repeated  every  hour  until  the  patient  reacts  from 
the  crisis  (usually  about  12  hours),  then  every  2 
to  3  hours  during  the  second  12-hour  period,  and 
subsequently  every  3  to  6  hours  until  the  patient 
is  afebrile  and  well.  In  addition  to  adrenal  cortex 
injection,  20  mg.  of  desoxycorticosterone  acetate 
in  oil  should  be  given  intramuscularly  immedi- 
ately, followed  by  a  dose  of  5  to  10  mg.  daily  until 
the  patient  is  well.  If  the  systolic  blood  pressure 
is  less  than  90  mm.  of  mercury,  epinephrine  or 
ephedrine  should  be  used  hypodermically.  If  the 
blood  pressure  remains  low,  whole  blood  or  plasma 
is  indicated  intravenously.  Oral  fluids  may  be 
permitted  as  tolerated.  Morphine  is  contraindi- 
cated. 

In  chronic  states  of  deficiency  or  after  recovery 
from  an  acute  crisis,  infection,  fasting  and  exces- 
sive stress  and  strain  must  be  avoided.  A  diet 
high  in  sodium  chloride  but  low  in  potassium  is 
indicated;  from  3  to  10  Gm.  of  sodium  chloride, 
as  enteric-coated  tablets,  should  be  administered 
daily.  Although  some  mild  cases  may  be  kept  in 
a  state  of  health  with  the  high  sodium  diet  only, 
the  majority  of  patients  will  require  some  form 
of  adrenal  cortical  hormone.  Desoxycorticosterone 
acetate,  which  regulates  only  the  water  and  salt 
metabolism,  may  suffice.  It  has  the  important 
virtue  of  being  cheaper  therapy;  implantation  of 
pellets  (see  under  Desoxycorticosterone  Acetate) 
about  once  a  year  is  often  effective  and  avoids 
repeated  injections.  Adrenal  cortical  extract, 
which  provides  the  carbohydrate  as  well  as  the 
water   and   salt   regulating   substances,   may   be 


30 


Adrenal   Cortex   Injection 


Part   I 


required  in  doses  as  high  as  15  to  20  ml.  intra- 
muscularly daily.  Cortisone  acetate  by  mouth  and 
extra  salt  in  the  diet  will  control  many  cases 
without  the  necessity  for  injections  of  desoxycor- 
ticosterone  or  adrenal  cortex  extract.  Therapy  is 
guided  by  the  disappearance  of  clinical  symptoms, 
weight  gain  and  the  maintenance  of  a  normal 
blood  pressure.  Infection  increases  the  amount  of 
cortical  hormone  needed. 

In  addition  to  the  treatment  of  Addison's  dis- 
ease, the  adrenal  steroid  hormones  have  been 
employed  with  benefit  in  the  management  of  the 
shock  of  severe  thermal  burns  (Scudder  and 
Elliott,  South.  Med.  Surg.,  1942,  104,  651)  and 
of  traumatic  or  surgical  shock  (Helfrich  et  al., 
Am.  J.  Surg.,  1942,  55,  410).  However,  Rhoads 
et  al.  {Ann.  Surg.,  1943,  118,  982)  reversed  their 
preliminary  impression  of  the  value  of  these 
hormones  in  the  shock  due  to  burns.  Likewise, 
Koster  and  Kagman  {Arch.  Surg.,  1941,  45,  2  724) 
denied  any  benefit,  in  surgical  shock.  Some  of  this 
controversy  doubtless  arose  from  the  use  of  the 
relatively  weak  extracts  which  were  available.  In 
the  Waterhouse-Friderichsen  syndrome  (acute 
adrenal  insufficiency  in  meningococcal  infections 
which  is  often  due  to  hemorrhage  into  the  adre- 
nals), early  diagnosis  and  vigorous  treatment  for 
the  Addisonian  crisis  may  alter  the  otherwise 
hopeless  prognosis  (Weinberg  and  McGavack, 
New  Eng.  J.  Med.,  1945.  232,  95).  Rich  (Bull. 
Johns  Hopkins  Hosp.,  1944,  74,  1)  has  shown 
that  adrenal  damage  also  plays  a  role  in  death 
from  severe  infections  with  streptococcus,  pneu- 
mococcus.  diphtheria  bacillus,  etc.  (see  also  Sara- 
son,  Arch.  Int.  Med.,  1943,  71,  702);  the  clinical 
use  of  adrenal  extracts  in  the  management  of 
serious  toxic  infections  (London  and  Holman, 
South.  M.  J.,  1945,  38,  596;  Perla  and  Marmors- 
ton.  Endocrinology,  1940,  27,  367;  Farah.  Lancet, 
1938,  1,  777)  seems  therefore  to  be  justified. 

In  alcoholism,  Tintera  and  Lovell  (Geriatrics, 
1949,  4,  274)  employed  the  extract  according  to 
the  regimen  used  for  the  crisis  of  Addison's  dis- 
ease on  the  basis  of  findings  indicating  that  adre- 
nal insufficiency  exists  in  such  patients;  recovery 
from  a  period  of  severe  alcoholism  was  speeded 
and  the  discomfort  was  minimized.  Voegtlin 
(Quart.  J.  Stud.  Alcohol,  1953,  14,  28)  confirmed 
initial  benefit  with  cortisone  and  corticotropin  but 
found  no  benefit  with  continued  use  in  preventing 
recurrence  of  alcoholic  excesses.  Adrenal  cortex 
injection  has  been  recommended  for  a  variety  of 
disorders  for  which  no  effective  therapy  is  avail- 
able. B 

Toxicology. — Toxic  effects  from  extracts  of 
adrenal  cortex  are  almost  unknown  (Gordon, 
J.A.M.A.,  1940,  114,  2549),  although  desoxycor- 
ticosterone  has  caused  serious  untoward  effects. 
If  the  intake  of  sodium  chloride  is  high,  edema 
may  develop  with  adrenal  cortex  extract.  Rapid 
intravenous  injection  of  5  ml.  or  more  causes  the 
effects  of  epinephrine  transiently  even  though  only 
traces  of  epinephrine  remain  in  most  extracts. 

Route  of  Administration. — Aqueous  ex- 
tracts of  adrenal  cortex,  which  are  usually  pre- 
pared from  beef  adrenal  glands,  are  readily  ab- 
sorbed on  subcutaneous  or  intramuscular  injec- 
tion; their  cortical  steroid  action  persists  for  1  to 


4  hours.  Although  the  adrenal  steroid  hormones 
are  absorbed  after  oral  administration  (Rogoff, 
J. A.M. A.,  1932,  99,  1309;  Grollman  and  Firor, 
/.  Biol.  Chem.,  1935,  109,  189),  this  route  of 
administration  has  seldom  proved  to  be  practical 
(Thorn  et  al.,  Endocrinology,  1938,  23,  403,  and 
see  also  under  Desoxycorticosterone  Acetate). 
There  is  no  apparent  therapeutic  value  in  the 
dried  suprarenal  gland  which  was  long  used  in 
medicine. 

The  usual  dose  of  adrenal  cortex  injection  is 
10  ml.,  intramuscularly  or  intravenously,  with  a 
range  of  10  to  100  ml.  The  dose  is  repeated  as 
often  as  necessary  (see  above  for  details).  The 
maximum  safe  dose  is  limited  by  the  trace  of 
epinephrine  (up  to  0.2  mg.  per  100  ml.)  remain- 
ing in  the  injection. 

Storage. — Preserve  "in  single-dose  or  in  mul- 
tiple-dose containers,  preferably  of  Type  I  glass. 
It  may  be  packaged  in  50-ml.  multiple-dose  con- 
tainers." U.S.P. 

Usual  Sizes. — 10  and  50  ml. 

AGAR.     U.S.P 

Agar-Agar,  [Agar] 

"Agar  is  the  dried  hydrophilic,  colloidal  sub- 
stance extracted  from  Gelidium  cartilagineum 
(Linne)  Gaillon  (Fam.  Gelidiacece),  Gracilaria 
confervoides  (Linnej  Greville  (Fam.  Sphcero- 
coccacem),  and  from  related  red  algae  (Class 
Rhodophycece) ."  U.S.P. 

Vegetable  Gelatin;  Japanese  or  Chinese  Gelatin;  Japanese 
Isinglass.  Gelosa.  Fr.  Gelose;  Colle  du  Japon.  Ger.  Agar 
agar;  Vegetabilischer  Fischleim;  Japanischer  Fischleim. 
Sp.  Agar-Agar;  Agar;  Gelosa. 

Quite  a  number  of  the  algae  belonging  to  the 
Rhodophycece,  growing  on  the  coast  of  southern 
and  eastern  Asia,  California,  and  the  Eastern 
United  States,  contain  large  quantities  of  mucilage 
which  is  extracted  and  sold  under  the  name  of 
agar-agar.  The  most  important  species  are  Geli- 
dium cartilagineum  (L.)  Gaillon.  Gelidium 
Amansii  Lamouroux,  Ahnjeltia  plicata  (Huds.) 
Fries,  Endocladia  muricata  (P.  &  B.)  J.  G.  Ag., 
Gracilaria  confervoides  (L.)  Greville,  and  Hypnea 
musciformis  (Wulfen)  Lamouroux.  The  algae  are 
usually  collected  during  the  summer  and  fall, 
bleached  or  unbleached,  and  dried,  but  the  process 
of  the  manufacture  of  agar-agar  does  not  take 
place  until  cold  weather,  and  usually  extends  from 
November   to   February. 

According  to  Tseng  (Sci.  Monthly,  1944,  59, 
37),  Gelidium  cartilagineum,  a  reddish-purple, 
fern-like  agarophyte,  occurs  from  Point  Concep- 
cion  southward  along  the  southern  California 
coast,  growing  on  rocks  from  the  low  tide  mark 
to  a  depth  of  30  or  more  feet.  It  is  chiefly  har- 
vested with  a  diving  rig,  the  diver  pulling  the  alga 
off  by  hand.  It  is  dried  in  the  sun  and  baled,  but 
not  bleached. 

In  processing  agar  in  California,  the  seaweed 
is  soaked  in  cleaning  vats  to  remove  sand,  etc., 
placed  in  pressure  cookers  where  the  amorphous 
gelatinous  substance  is  dissolved  from  the  plants 
by  hot  water,  then  the  resultant  hot  solution 
passed  through  filter  presses  to  tubs  where  it 
forms  a  gel  on  cooling.  The  gel  is  crushed  and 


Part  I 


Agar 


31 


poured  into  cans  in  the  freezing  room ;  the  frozen 
gel  is  thawed,  and  the  cold  water  containing  im- 
purities is  separated  from  the  agar  particles  in 
rotary  vacuum  filters.  The  agar  flakes  resulting 
are  then  carried  to  huge  cylindrical  stack  driers 
where  they  are  dried  by  ascending  currents  of  hot 
air.  Along  the  coast  of  Japan  the  species  yielding 
agar  are  cultivated,  poles  being  anchored  in  the  sea 
to  provide  supports  upon  which  they  multiply. 
The  poles  are  withdrawn  and  the  algae  stripped  off, 
taken  ashore,  and  dried,  then  beaten  to  remove 
sand  and  shells,  and  bleached  by  alternate  wash- 
ing and  exposure  to  sunlight  preparatory  to  ex- 
tracting the  gelose. 

Wood  (/.  Council  Sci.  Ind.  Res.,  1942,  15, 
295)  reported  that  Gracilaria  confervoides  is  the 
most  abundant  source  of  agar  in  Australia.  There 
the  algae  are  gathered  from  sandy  flats,  sometimes 
bleached  on  grass,  washed  with  beaters  to  remove 
sand,  minced,  cooked  with  live  steam  for  2  to  4 
hours  at  95°  to  98°,  using  4  per  cent  of  the  algae 
in  the  digestion  liquid,  and  adjusting  the  reaction 
to  pH  5  to  6.  Solids  are  removed  from  the  hot 
liquid  by  centrifuging  or  by  filtration  through 
steam  heated  bag  filters;  the  clarified  liquid  is 
run  into  a  steam  pan,  treated  with  activated  char- 
coal and  filtered  through  a  plate  and  frame 
press.  The  colorless  liquid  is  concentrated  at  a 
low  temperature  and  allowed  to  set  at  21°,  effect- 
ing separation  of  certain  organic  impurities.  The 
resultant  gel  is  thawed  at  35°,  washed  in  running 
water  and  dried  at  40°  to  50°  in  a  tunnel  drier. 

Most  of  the  agar  used  in  the  United  States  be- 
fore World  War  II  was  imported  from  Japan,  al- 
though considerable  is  produced  from  red  algae 
growing  along  the  coast  of  lower  California.  In 

1952,  the  U.  S.  imported  337,240  pounds  of  agar, 
most  of  which  came  from  Japan  and  the  Korean 
Republic.  During  the  last  war  production  of 
Pacific  agar  in  California  was  greatly  increased 
and,  in  addition,  large  amounts  of  so-called 
"Atlantic  coast  agar"  were  manufactured  from 
Gracilaria  confervoides  (L).  Greville  and  allied 
species  of  red  algae  gathered  off  the  coast.  By 

1953,  production  of  Atlantic  coast  agar  had 
greatly  increased  and  it  now  represents  consider- 
able of  the  American  drug. 

The  following  varieties  of  agar  are  known: 

1. — Ceylon  Agar-agar,  consisting  chiefly  of 
Gracilaria  lichenoides,  Greville,  the  alga  used  by 
the  Hirundo  esculenta  in  the  formation  of  its 
edible  nest. 

2. — Macassar  Agar-agar,  coming  from  the 
straits  between  Borneo  and  Celebes,  consisting 
of  impure  Eucheuma  spinosum,  Ag.,  incrusted 
with  salt. 

3. — American  Agar-agar,  derived  from  red  algae 
growing  in  the  Pacific  Ocean  off  the  coast  of  Cali- 
fornia, including  Gelidiutn  cartilagineum,  G. 
Amansii  and  Ahnfeltia  plicata,  which  yield  the 
product  known  as  "Pacific  Coast  Agar"  and  from 
red  algae  growing  in  the  Atlantic  Ocean  off  the 
coast  of  southern  U.  S.  and  Massachusetts,  in- 
cluding Gracilaria  confervoides  and  Hypnea  mus- 
ciformis,  which  yield  the  "Atlantic  Coast  Agar." 

4. — Japanese  Agar-agar,  known  as  Japanese 
isinglass,  derived  from  a  number  of  algae,  espe- 
cially Sphoerococcus  compressus,  Ag.,  Gloiopeltis 


tenax,  J.  Ag.,  G.  cartilagineum  (L.)  Gaill.  and 
other  species  of  Gelidium.  Japanese  agar  differs 
chiefly  from  American  agar  by  containing  the 
large  discoid  diatom,  Arachnoidiscus  Ehrenbergii 
Baill.  Both  varieties  contain  other  species  of 
diatoms  and  sponge  spicules. 

5. — Australian  Agar-agar,  yielded  by  Gracilaria 
confervoides. 

Constituents. — Agar  is  composed  mainly  of 
the  calcium  salt  of  a  complex  carbohydrate  sub- 
stance commonly  called  gelose.  Percival  and 
Somerville  (/.  Chem.  S.,  1937,  1615)  were  the 
first  to  establish  the  structural  characteristics  of 
the  carbohydrate  component;  they  showed  the 
major  part  of  it  to  consist  of  D-galactose  residues 
united  by  1,3-glycosidic  linkages  chiefly  of  the 
P-type.  The  presence  of  L-galactose  as  well  as  of 
an  esterified  sulfuric  acid  group  was  also  estab- 
lished. Jones  and  Peat  (/.  Chem.  S.,  1942,  225) 
consider  the  chief  constituent  of  agar  to  be  the 
sulfuric  acid  ester  of  a  linear  polygalactose  in 
which  the  repeating  unit  is  composed  of  nine 
D-galactopyranose  residues  terminated  at  the  re- 
ducing end  by  one  residue  of  L-galactose.  The 
D-galactose  units  are  mutually  combined  by  1,3- 
glycosidic  linkages,  but  the  L-galactose  residue  is 
attached  to  the  chain  through  position  4;  this 
residue  is  esterified  at  the  sixth  carbon  atom  with 
sulfuric  acid.  Percival  and  Thomson  (/.  Chem.  S., 
1943,  750)  reported  analytical  data  on  the  hy- 
drolysis of  certain  agar  derivatives  which  are  at 
variance  with  those  of  Jones  and  Peat  and  are 
of  the  opinion  that  the  structure  proposed  by  the 
latter   investigators   is    oversimplified. 

Itano  (Proc.  Imp.  Acad.  Tokyo,  1933,  9,  398) 
found  that  commercial  agar  may  contain  from 
24.5  to  101.9  parts  per  million  of  iodine.  This 
may  be  reduced  to  6  or  7  p.p.m.  by  suitable 
purification. 

When  a  solution  of  agar  is  cooled,  even  that 
of  1  in  500  parts  of  water  a  colorless,  trans- 
parent, and  stiff  jelly  is  obtained,  which,  when 
heated  with  moderately  strong  nitric  acid,  yields 
mucic  and  oxalic  acids.  It  dissolves  on  heating 
with  acidulated  water  without  yielding  a  jelly  on 
cooling. 

Description. — "Unground  Agar  usually  oc- 
curs in  bundles  consisting  of  thin,  membranous, 
agglutinated  pieces  or  in  cut,  flaked  or  granulated 
forms.  It  may  be  externally  weak  yellowish 
orange,  yellowish  grc.y  or  pale  yellow  or  colorless. 
It  is  tough  when  damp,  brittle  when  dry.  It  is 
odorless  or  has  a  slight  odor  and  a  mucilaginous 
taste. 

"Histology. — In  water  mounts  Agar  appears 
granular  and  somewhat  filamentous;  a  few  frag- 
ments of  the  spicules  of  sponges  and  a  few  frus- 
tules  of  diatoms  may  be  present;  in  Japanese 
Agar,  the  frustules  of  Arachnoidiscus  Ehrenbergii 
Baillon  occur,  which  are  disc-shaped  and  from 
100  to  300  \i  in  diameter. 

"Powdered  Agar  is  white  to  yellowish  white  or 
pale  yellow;  in  chloral  hydrate  T.S.  its  fragments 
are  transparent,  more  or  less  granular,  striated, 
angular,  and  occasionally  containing  frustules  of 
diatoms. 

"Solubility. — Agar  is  insoluble  in  cold  water, 
but  soluble  in  boiling  water."  U.S.P. 


32  Agar 


Part  I 


Standards  and  Tests. — Identification. — (1) 
Some  fragments  of  agar  are  colored  bluish  black, 
and  some  areas  reddish  to  violet,  by  iodine  T.S. 
(2)  On  boiling  agar  with  65  times  its  weight  of 
water  for  10  minutes,  with  constant  stirring,  then 
adjusting  to  1.5  per  cent  concentration  of  agar  by 
addition  of  hot  water,  a  clear  liquid  results;  at 
32"  to  39°  it  congeals  to  form  a  firm,  resilient  gel, 
the  melting  point  of  which  is  not  below  85°. 
Water. — Not  over  20  per  cent  when  determined 
by  drying  at  105°  for  5  hours.  Acid-insoluble  ask. 
— Not  over  0.5  per  cent,  on  a  dry  weight  basis. 
Total  ash. — Not  over  6.5  per  cent,  on  a  dry  weight 
basis.  Foreign  organic  matter. — Not  over  1  per 
cent.  Foreign  insoluble  matter. — When  calculated 
on  a  dry  weight  basis  not  over  1  per  cent  of  resi- 
due is  obtained  by  filtering  a  solution  of  1.5  Gm. 
of  agar  in  200  ml.  of  hot  aqueous  solution  through 
a  Gooch  crucible  and  drying  the  latter  at  105°. 
Foreign  starch. — No  blue  color  is  produced  on 
adding  iodine  T.S,  to  a  solution  prepared  by  boil- 
ing 100  mg.  of  agar  with  100  ml.  of  water,  then 
cooling.  Gelatin. — No  turbidity  develops  in  10 
minutes  following  addition  of  5  ml.  of  picric  acid 
T.S.  to  an  equal  volume  of  a  solution  made  by 
dissolving  1  Gm.  of  agar  in  100  ml.  of  boiling 
water  and  cooling  to  about  50°.  Water  absorption. 
— 5  Gm.  of  agar  is  placed  in  a  100-ml.  graduated 
cylinder  and  enough  water  added  to  the  100  ml. 
mark;  after  24  hours  of  maceration  at  25°  not 
more  than  75  ml.  of  water  should  be  obtained  by 
pouring  off  the  liquid,  through  glass  wool,  into 
another  graduated  cylinder,  corresponding  to  the 
absorption  by  agar  of  at  least  five  times  its  weight 
of  water.  U.S.P. 

Tseng  (Science,  1945,  101,  597)  observed  that 
it  is  not  yet  definitely  known  whether  the  so- 
called  agar  from  sources  (agarophytes)  other  than 
species  of  Gelidium  is  identical  with  the  latter. 
He  suggested  that  a  definition  or  specification  for 
agar  should  include  the  requirement  that  a  one 
per  cent  neutral,  aqueous  solution  of  it  should 
set  at  35°  to  50°  to  a  firm  gel,  and  the  latter 
melt  at  80°  to  100°.  Tseng  also  proposed  the  new 
term  phycocolloid  to  designate  the  polysaccharides 
which  are  derived  from  the  brown  and  the  red 
seaweeds  and  which  are  able  to  form  colloidal 
systems  when  dispersed  in  water. 

The  presence  of  Japanese  agar  may  often  be 
detected  by  the  characteristic  diatoms;  a  proce- 
dure based  on  this  was  described  by  Schneider 
(Pac.  Pharm.,  1912,  p.  35).  Identification  meth- 
ods utilizing  characteristic  color  and  precipitation 
reactions  are  described  by  Cannon  (J.A.O.A.C., 
1939,  22,  92,  726)  and  by  Pirie  (Brit.  J.  Exp. 
Path.,  1936.  17,  269). 

Uses. — The  therapeutic  value  of  agar  is  de- 
pendent on  its  ability  to  absorb  and  retain  water 
as  it  passes  through  the  gastrointestinal  tract, 
giving  bulk  to  the  intestinal  contents  and  also 
serving  as  a  lubricant.  Its  mechanical  action  is. 
therefore,  analogous  to  that  of  the  cellulose  of 
vegetable  foods.  Because  it  aids  in  maintaining 
regularity  of  bowel  movements,  agar  has  been 
widely  used  in  the  treatment  of  chronic  constipa- 
tion. It  is  frequently  combined  with  cascara  or 
some  other  vegetable  cathartic  because  it  is  com- 
monly believed  that  agar  does  not  stimulate  peri- 


stalsis in  atonic  intestinal  muscle,  although  Chase, 
cited  by  Tseng  (Sci.  Monthly,  1944,  58,  24), 
stated  that  it  does  contain  laxative  principles 
which  excite  peristaltic  activity.  Eisner  et  al. 
(Ztschr.  physiol.  Chem.,  1937,  246,  244)  re- 
ported that  agar  is  an  anticoagulant. 

Agar  is  best  administered  in  the  form  of  a  gel, 
prepared  by  dissolving  it  in  hot  water  and  cool- 
ing, flavored  and  sweetened  as  desired;  at  body 
temperature  agar  absorbs  little  water  and  does 
not  provide  much  more  bulk  than  when  dry 
(Gray  and  Tainter,  Am.  J.  Digest.  Dis.,  1941, 
8,  130).  It  is,  however,  also  commonly  cut  into 
small  pieces  and  eaten  like  cereal;  chocolate- 
coated  preparations  of  agar  have  been  marketed. 
In  many  proprietary  preparations  it  is  combined 
with  mineral  oil  as  an  emulsion;  in  such  prepara- 
tions the  agar  serves  primarily  as  an  emulsifying 
agent  and,  although  the  character  of  the  stool  is 
modified,  little  is  added  to  the  bulk  (Nelson, 
Internat.  Med.  Digest,  1943,  42,  308)  because 
of  the  relatively  small  amount  of  agar  present. 

Agar  is  much  used  in  the  preparation  of  suspen- 
sions, emulsions,  jellies,  hydrophilic  suppositories, 
etc.  For  years  it  has  served  as  the  basis  of  many 
culture  media  employed  by  bacteriologists.  War- 
time dearth  of  supply  stimulated  development  of 
methods  for  recovering  agar  from  used  culture 
media  (Blundell,  Science,  1943,  97,  76;  Brodie 
and  Stiven,  /.  Hygiene,  1942,  46,  498).  Agar  is 
used  as  food  in  the  Orient;  while  it  contains  60 
per  cent  of  carbohydrates  the  latter  consist  largely 
of  indigestible  hemicelluloses  which  may  actually 
decrease  absorption  of  the  nutrient  substances 
that  are  present.  Agar  is  also  extensively  used  in 
bakery  products,  in  clarifying  liquids,  in  making 
"health  foods,"  in  confections,  and  in  ice  cream. 
In  dentistry  it  serves  as  an  impression  mold.  For 
further  information  concerning  uses  of  agar  see 
Tseng   (Sci.  Monthly,   1944,   58,   24;    1944,   59, 

37).  m 

Dose. — The  usual  dose  is  4  Gm.  (approxi- 
mately 60  grains)  once  or  twice  daily;  the  range 
of  dose  is  4  to  16  Gm. 

Off.  Prep. — Phenolphthalein  in  Liquid  Petro- 
latum Emulsion,  N.F. 


NORMAL  HUMAN  SERUM 
ALBUMIN.     U.S.P. 

Normal  Serum  Albumin  (Human),   [Albuminum  Seri 
Humanum  Normale] 

"Normal  Human  Serum  Albumin  is  a  sterile 
preparation  of  serum  albumin  obtained  by  frac- 
tionating blood  from  healthy,  human  donors.  It  is 
either  a  solution  containing,  in  each  100  ml.,  25 
Gm.  of  the  serum  albumin  osmotically  equivalent 
to  500  ml.  of  normal  human  plasma,  or  a  dried 
preparation  suitable  for  restoration  to  an  appro- 
priate volume  for  clinical  use.  It  contains  no 
added  bacteriostatic  agent,  but  each  100  ml.  of 
the  liquid  form  may  contain  as  a  stabilizing 
agent  either  0.04  mol  of  sodium  acetyltryptopha- 
nate  or  0.02  mol  each  of  sodium  acetyltryptopha- 
nate  and  sodium  caprylate.  If  prepared  from 
plasma  containing  a  mercurial  preservative,  it 
contains  not  more  than  20  meg.  of  mercury  per 
Gm.  of  albumin.  Not  less  than  97  per  cent  of  the 


Part  I 


Albumin,   Normal    Human   Serum  33 


total  protein  of  Normal  Human  Serum  Albumin 
is  albumin."  U.S.P. 

Normal  human  serum  albumin  is  obtained  by 
fractionation  of  human  plasma  and  constitutes  up 
to  90  per  cent  of  fraction  V  (for  further  informa- 
tion see  Normal  Human  Plasma). 

Description. — "Liquid  Normal  Human  Serum 
Albumin  is  a  moderately  viscous,  clear,  brownish 
fluid.  It  is  substantially  odorless.  Dried  Normal 
Human  Serum  Albumin  has  a  light  yellow  to  deep 
cream  color."  U.S.P. 

Standards  and  Tests. — Sodium  content. — 
Not  more  than  0.0132  Gm.  of  Na  per  Gm.  of 
albumin.  Water  content  of  dried  serum  albumin. 
— Not  over  1  per  cent,  when  determined  by  drying 
to  constant  weight  at  room  temperature  over 
phosphorus  pentoxide  at  a  pressure  of  not  more 
than  1  mm.  of  mercury.  Other  requirements. 
— Complies  with  the  identity,  safety,  sterility, 
and  stability  tests  and  other  requirements  of  the 
National  Institutes  of  Health  of  the  United  States 
Public  Health  Service,  including  the  release  of 
each  lot  individually  before  its  distribution.  U.S.P. 

Uses. — Human  serum  albumin  was  developed 
during  World  War  II  as  a  compact,  stable,  easily 
transportable  blood  substitute  for  use  in  emer- 
gency treatment  of  shock  (see  under  Normal 
Human  Plasma).  When  its  use  was  later  ex- 
tended to  include  treatment  of  hypoproteinemic 
states  and  nephrosis,  a  salt-poor  form  was  pre- 
pared in  which  the  sodium  content  is  one-seventh 
or  less  than  that  of  an  osmotically  equivalent  vol- 
ume of  plasma.  Heating  to  60°  for  10  hours  de- 
stroys the  virus  of  serum  hepatitis  and  also 
bacteria  so  that  mercurial  preservatives  are  no 
longer  needed.  Use  of  human  albumin  intrave- 
nously does  not  carry  the  risk  of  homologous 
serum  hepatitis  that  exists  when  pooled  plasma 
or  serum  is  used  and  to  a  lesser  extent  with 
single  blood  donations  (Paine  and  Janeway, 
J.A.M.A.,  1952,  150,  199). 

Shock. — In  emergency  treatment  of  shock 
serum  albumin  is  of  unquestioned  value.  An  in- 
crease in  plasma  volume  of  8  to  18  ml.  for  each 
Gm.  of  albumin  administered  is  to  be  expected 
but  extra  fluid  must  be  given  to  dehydrated  pa- 
tients to  achieve  maximum  benefit  (Gibson,  New 
Eng.  J.  Med.,  1948,  239,  579).  Human  serum 
albumin  does  not  restore  loss  of  oxygen-carrying 
capacity  resulting  from  loss  of  blood  due  to 
hemorrhage. 

Nephrosis. — Serum  albumin  has  been  used  ex- 
tensively in  the  nephrotic  syndrome,  but  with  dis- 
appointing results.  Seegal  and  Wertheim  (Bull. 
N.  Y.  Acad.  Med.,  1949,  25,  605)  reported  ob- 
servations on  81  patients  given  103  courses  of 
albumin  under  well-controlled  conditions.  Daily 
doses  varied  from  7.5  to  100  Gm.  Transient  and 
incomplete  diuresis  was  seen  in  47  per  cent  of 
treatments;  questionable  effect  was  noted  in  10 
per  cent;  no  diuresis  was  found  in  the  remaining 
43  per  cent.  Most  of  the  injected  albumin  ap- 
peared in  the  urine  in  24  hours.  Such  therapy  did 
not  affect  the  natural  course  of  the  underlying 
disease.  Janeway  (J.A.M.A.,  1948,  138,  864) 
concluded  that  the  place  of  albumin  in  the  ther- 
apy of  nephrosis  is  limited,  that  its  use  is  enor- 
mously wasteful  and  expensive,  and  that  it  does 


not  alter  the  course  of  the  disease.  However,  in 
certain  cases  in  which  other  methods  of  therapy 
fail,  and  in  which  edema  is  incapacitating,  he  has 
found  it  useful. 

Cirrhosis  of  the  Liver. — Conflicting  reports 
have  appeared  on  the  use  of  albumin  in  cirrhosis. 
Kunkel  et  al.  (I.  Clin.  Inv.,  1948,  27,  305)  treated 
17  patients  with  doses  of  100  to  2000  Gm.  of 
albumin.  Patients  with  low  serum  albumin  and 
ascites  of  short  duration  responded  most  readily, 
although  14  of  15  patients  with  ascites  eventually 
lost  their  fluid  after  albumin  therapy.  With 
smaller  doses  for  shorter  periods,  Thorn  et  al. 
(ibid.,  1946,  25,  304)  and  Patek  et  al.  (ibid., 
1948,  27,  135)  were  unable  to  produce  a  favor- 
able result.  Falcon  and  coworkers  (ibid.,  1949, 
28,  583)  saw  3  fatal  hemorrhages  from  esophageal 
varices  shortly  after  giving  albumin  to  20  cirrhotic 
patients.  Jacobi  et  al.  (J.  Pediatr.,  1946,  29,  177) 
found  an  excellent  response  in  2  infants  with 
erythroblastosis  fetalis  and  edema  following  ad- 
ministration of  30  and  12.5  Gm.  of  albumin, 
respectively.  Post  et  al.  (Arch.  Int.  Med.,  1951, 
87,  775)  used  salt-poor  human  albumin  intrave- 
nously in  patients  critically  ill  with  decompen- 
sated hepatic  cirrhosis  with  general  clinical  im- 
provement, gain  in  appetite,  strength  and  body 
tissue,  as  well  as  decline  of  icterus  along  with  the 
diuresis.  They  concluded  that  albumin  has  a  place 
in  the  management  of  patients  with  severely  de- 
compensated hepatic  cirrhosis  for  whom  adequate 
dietary  therapy  cannot  be  provided.  Ricketts  et 
al.  (J.  Clin.  Inv.,  1951,  30,  1157)  found  that 
albumin  intravenously  did  not  correct  the  de- 
creased renal  excretion  of  sodium  in  these  cases; 
the  albumin  increased  in  the  ascitic  fluid  and 
tissue  edema  fluid  moved  to  the  abdominal  peri- 
toneal space.  Abnormal  capillary  permeability 
during  the  active  disease  is  probably  a  factor. 

The  final  evaluation  of  the  place  of  albumin  in 
therapy  must  await  definitive  studies  of  the  me- 
tabolism of  injected  albumin  in  normal  and  ab- 
normal states.  This  agent  has  potent  osmotic 
activity  the  extent  of  which  depends  upon  the 
state  of  protein  nutrition  and  the  permeability  of 
capillaries  throughout  the  body  and  especially  in 
the  glomerulus.  There  is  no  evidence  of  renal 
damage  from  increased  proteinuria.  A  positive 
nitrogen  balance  following  administration  of  albu- 
min may  merely  mean  inert  retention  in  extra- 
cellular fluid  rather  than  actual  metabolism. 

Studies  with  albumin  tagged  with  radioactive 
iodine-131  demonstrated  that  depletion  of  labile 
albumin  stores  can  be  correlated  with  presence  of 
ascites  (Tyor  and  Gayer,  South.  M.  J.,  1952,  45, 
144) ;  it  is  suggested  that  albumin  metabolism 
proceeds  at  a  constant  rate  and  is  demonstrably 
altered  only  in  the  terminal  stages  of  liver  dis- 
ease. Albumin  tagged  with  iodine-131  has  also 
been  used  for  the  study  of  peripheral  circulation 
(Krieger  et  al.,  Ann.  Surg.,  1952,  136,  357). 

The  usual  dose,  intravenously,  is  100  to  200 
ml.,  representing  25  to  50  Gm.  of  albumin,  re- 
peated as  necessary.  In  terms  of  body  weight  the 
dose  is  2.2  ml.  per  Kg.,  injected  at  a  rate  of  2  ml. 
per  minute. 

Labeling. — "The  container  label  bears  the 
name   Normal  Serum   Albumin    (Human);    the 


34  Albumin,   Normal    Human   Serum 


Part   I 


amount  in  Gm.  of  albumin  present;  in  the  case  of 
liquid  serum  albumin  the  total  volume  of  the 
contents  and  the  amount  and  kind  of  stabilizing 
agent;  the  osmotic  equivalent  in  terms  of  plasma; 
the  lot  number;  the  expiration  date,  which  for 
liquid  serum  albumin  is  not  more  than  5  years 
after  date  of  manufacture  or  date  of  issue,  and 
for  dried  serum  albumin  not  more  than  8  years 
after  date  of  manufacture  or  date  of  issue;  the 
manufacturer's  name;  the  statement,  'Contains  no 
preservative';  and  in  the  case  of  liquid  serum 
albumin  the  statements,  'Caution:  Do  not  use  if 
turbid,'  and  'Salt  Poor.  Additional  fluids  are  re- 
quired when  administered  to  patient  with  marked 
dehydration,'  and  in  the  case  of  dried  serum  albu- 
min the  statement,  'Use  within  3  hours  after  res- 
toration.' The  package  label  bears,  in  addition  to 
the  above,  the  manufacturer's  license  number 
and  address,  and  the  recommended  storage  tem- 
perature." U.S.P. 

Storage. — Preserve  "at  a  temperature  between 
2°  and  10°.  Exposure  for  short  periods  to  a  higher 
temperature  will  cause  no  significant  deterioration. 
Preserve  dried  Normal  Human  Serum  Albumin 
at  room  temperature,  not  exceeding  37°.  Dis- 
pense Normal  Human  Serum  Albumin  in  the 
unopened  container  in  which  it  was  placed  by  the 
manufacturer."  U.S.P. 

Usual  Sizes. — 20  and  50  ml.,  equivalent  to 
100  and  250  ml.  of  plasma. 

ALCOHOL.    U.S.P,.  B.P.  (LP.) 

Ethanol,  Ethyl  Alcohol,  Spiritus  Vini  Rectificatus, 
[Alcohol] 

CH3.CH2OH 

"Alcohol  contains  not  less  than  92.3  per  cent  by 
weight,  corresponding  to  94.9  per  cent  by  volume, 
at  15.56°,  of  C2H5OH."  U.S.P.  The  B.P.  requires 
from  94.7  per  cent  to  95.2  per  cent  v/v  (92.0  to 
92.7  per  cent  w/w)  of  C2H6O.  The  LP.  requires 
Ethanol  to  contain  not  less  than  95.1  per  cent 
v/v  and  not  more  than  96.8  per  cent  v/v,  corre- 
sponding to  not  less  than  92.5  per  cent  w.  w  and 
not  more  than  95.0  per  cent  w/w  of  C2H5OH. 

Ethyl  Hydroxide;  Rectified  Spirit;  Spirit  of  Wine. 
Spiritus  Rectificatus;  Spiritus.  Fr.  Alcool  ethylique  a  95 
degres  centesimaux;  Alcool  officinal.  Ger.  Weingeist;  Al- 
kobol;  Athylalkohol ;  Branntwein.  It.  Alcool  rettificato; 
Spirito  di  vino.  Sp.  Alcohol;  Espiritu  de  vino. 

Alcohol  has  been  made  for  many  centuries  by 
the  fermentation  of  carbohydrates  by  yeast. 
Utilizable  carbohydrate-containing  materials  in- 
clude molasses,  sugar  cane,  fruit  juices,  corn, 
barley,  wheat,  potato,  wood  and  waste  sulfite  liq- 
uors. As  yeast  is  capable  of  fermenting  only 
D-glucose,  D-fructose,  D-mannose,  and  D-galactose 
it  is  essential  that  more  complex  carbohydrates 
be  converted  to  one  or  more  of  these  simple 
sugars  before  they  can  be  fermented.  This  is 
variously  accomplished;  for  example,  yeasts  con- 
tain enzymes  which  hydrolyze  disaccharides  to 
monosaccharides,  starches  may  be  saccharified  by 
hydrolysis  with  acids  or  by  the  enzyme  diastase 
from  malt,  cellulose  is  converted  to  sugars  by 
hydrolysis  with  acid  under  pressure. 

The  net  reaction  that  occurs  when  a  hexose, 
glucose  for  example,  is  fermented  to  alcohol  may 


be  represented  as  follows:  CeHi20ff-»2C2H50H-f 
2CO2.  The  mechanism  of  the  process  is,  however, 
exceedingly  complex  and  many  investigators  have 
studied  it  in  detail.  Of  the  several  theories  which 
have  been  proposed,  that  of  Meyerhof  is  sup- 
ported by  considerable  experimental  evidence. 
According  to  this  theory,  both  glucose  and  fruc- 
tose are  by  several  steps  converted  to  the  common 
intermediate  substance  fructose- 1,6-diphosphoric 
acid,  the  phosphoric  acid  being  supplied  through 
the  "adenylic  acid  system"  of  yeast.  The  fruc- 
tose-l,6-diphosphoric  acid  is  enzymatically  split 
into  an  equilibrium  mixture  of  the  three-carbon 
molecules  3-glyceraldehyde  phosphate  and  dihy- 
droxyacetone  phosphate,  which  are  isomeric  and 
convertible  one  into  the  other.  In  the  main 
sequence  of  fermentation  reactions  the  former 
substance  is  successively  converted  to  3-phospho- 
gly eerie  acid,  2-phosphoglyceric  acid,  phospho- 
pyruvic  acid  and  pyruvic  acid,  which  last  under- 
goes decarboxylation  to  acetaldehyde  and  then,  in 
a  reaction  involving  a  molecule  of  3-glyceralde- 
hyde phosphate,  is  enzymatically  reduced  to  ethyl 
alcohol.  A  minor  sequence  of  reactions,  leading 
to  the  production  of  a  small  amount  of  glycerin, 
starts  with  dihydroxyacetone  phosphate  which  is 
first  reduced  to  alpha-glycerol  phosphate  and  then 
dephosphorylated  to  glycerin.  Fusel  oil  and  suc- 
cinic acid  are  also  obtained  in  very  small  amounts. 
Formation  of  both  constituents  appears  to  be 
associated  with  nitrogen  metabolism  of  the  yeast 
cell  and  is  minimized  if  a  readily  available  source 
of  nitrogen  is  present  in  the  fermentation  mixture. 
The  chief  constituents  of  fusel  oil  are  isoamyl 
alcohol  and  D-amyl  (active  amyl)  alcohol. 

In  the  years  immediately  before  World  War  II 
approximately  90  per  cent  of  the  alcohol  pro- 
duced in  the  United  States  utilized  black-strap 
molasses  as  the  starting  material.  Manufacture 
of  alcohol  from  molasses  is  much  simpler  than 
from  grain  in  that  the  milling,  cooking  and  malt- 
ing (by  which  saccharification  of  starch  is  accom- 
plished) are  omitted;  molasses  does  not  require 
an  initial  hydrolysis  as  it  contains  fermentable 
sugars.  The  process  consists  of  the  following 
steps:  (1)  weighing  of  the  molasses,  (2)  mixing 
with  water,  (3;  sterilizing,  to  prevent  contami- 
nation with  organisms  which  may  influence  the 
course  of  the  fermentation,  (4)  cooling  or  dilut- 
ing with  cold  water,  (5)  charging  the  fermenters 
with  the  dilute  molasses,  (6)  addition  of  pure 
yeast  culture  (generally  Saccharomyces  cerevisia), 
sulfuric  acid  (to  invert  the  sucrose  in  the  mo- 
lasses), and  yeast  food  (ammonium  sulfate),  (7) 
fermentation  for  36  to  48  hours,  (8)  distillation 
of  the  "beer,"  which  contains  6.5  to  8.5  per  cent 
by  volume  of  alcohol,  to  yield  a  distillate  contain- 
ing 95  per  cent  by  volume  of  alcohol. 

Ethyl  alcohol  from  cellulose  was  first  produced 
commercially  in  this  country  during  1910,  in  a 
plant  constructed  for  this  purpose  in  South  Caro- 
line. Approximately  20  gallons  of  alcohol  was 
produced  from  each  ton  of  sawdust;  the  latter 
was  hydrolyzed  by  sulfuric  acid  under  pressure. 
A  process  developed  by  the  German  Bergius  in- 
creases the  yield  to  75  to  80  gallons  per  ton  of 
wood.  A  plant  under  construction  at  Springfield, 
Oregon,  had  been  planned  to  have  a  capacity  of 


Part  I 


Alcohol 


35 


about  11,500  gallons  of  alcohol  daily  from  some 
230  tons  of  wood  waste;  construction  of  it  was 
stopped  at  the  close  of  World  War  II. 

At  present,  approximately  half  of  the  total  in- 
dustrial alcohol  production  is  by  synthesis  in- 
volving hydration  of  ethylene.  Abundant  supplies 
of  ethylene  are  obtained  from  natural  and  coke 
oven  gases,  from  waste  gases  of  the  petroleum 
industry,  and  from  pyrolysis  of  ethane,  propane, 
and  butane.  The  older  and  by  far  the  more  widely 
used  synthesis  involves  indirect  hydration  of 
ethylene;  in  this  process  ethylene  is  reacted  with 
concentrated  sulfuric  acid  to  form  ethyl  hydrogen 
sulfate  and  dimethyl  sulfate,  both  of  which  react 
with  water  to  yield  ethyl  alcohol  and  sulfuric 
acid.  This  indirect  process  was  developed  because 
the  process  of  direct  hydration  originally  em- 
ployed was  slow.  Recently,  however,  direct  hydra- 
tion has  become  feasible  through  use  of  high 
pressures,  low  temperatures,  suitable  catalysts 
(such  as  aluminum  oxide),  and  by  recycling  of 
reactant  gases.  It  is  expected  that  production  of 
alcohol  from  ethylene  will  increase,  not  only  be- 
cause of  the  growing  availability  of  ethylene  but 
also  because,  when  molasses  prices  are  high,  alco- 
hol can  be  produced  more  cheaply  from  ethylene 
than  from  any  other  raw  material. 

In  another  synthesis  acetylene  is  catalytically 
hydrated  to  acetaldehyde,  which  is  then  hydro- 
genated,  in  the  presence  of  a  catalyst,  to  ethyl 
alcohol;  this  process  was  used  during  World 
War  I. 

The  term  proof  spirit,  as  used  in  the  United 
States,  refers  to  a  product  containing  50  per  cent 
by  volume  of  C2H5OH;  it  is  sometimes  desig- 
nated as  100  proof  alcohol.  The  strength  of  any 
other  solution  of  ethyl  alcohol  may  be  expressed 
in  "proof"  by  multiplying  the  concentration  of 
C2H5OH,  by  volume,  by  two.  Thus  an  alcohol 
containing  60  per  cent  by  volume  of  C2H5OH 
is  120  proof,  and  official  alcohol  of  95  per  cent 
by  volume  concentration  of  C2H5OH  is  190 
proof.  English  proof  spirit  contains  49.3  per  cent 
C2H5OH  by  weight,  or  57  per  cent  by  volume; 
it  is  materially  stronger  than  United  States  proof 
spirit. 

Alcohol  represents  a  constant-boiling  mixture 
of  ethanol  (95.57  per  cent  by  weight)  and  water 
(4.43  per  cent  by  weight) ;  the  boiling  point  is 
78.2°,  while  anhydrous  alcohol  boils  at  78.3°.  It  is 
not  possible  to  obtain  anhydrous  alcohol  by  direct 
distillation  (see  Dehydrated  Alcohol). 

Alcohol  has  many  and  varied  industrial  uses. 
It  is  important  as  a  general  solvent,  and  is  in- 
dispensable for  dissolving  perfumes,  flavoring  ex- 
tracts, and  in  the  preparation  of  pharmaceuticals. 
In  addition  it  is  essential  in  the  synthesis  of  many 
organic  substances,  including  ether  and  chloro- 
form. It  serves  as  a  fuel,  either  liquid  or  in  the 
form  of  "solidified  alcohol,"  and  has  been  used 
alone  or  mixed  with  gasoline  as  a  motor  fuel. 
"Solidified  alcohol"  contains  5  per  cent  methanol. 

Denatured  Alcohol. — The  U.  S.  government 
has  established  regulations  authorizing  the  addi- 
tion of  substances  to  alcohol  which  render  it  unfit 
for  beverage  purposes  although  it  is  suitable  for 
industrial  use.  The  liquid  so  treated  is  termed 
denatured  alcohol. 


The  U.  S.  Internal  Revenue  Department  has 
authorized  the  use  of  a  number  of  substances  for 
denaturing  alcohol,  but  such  alcohol  must  be  pre- 
pared under  the  supervision  of  an  official  of  the 
Department,  at  specified  depots.  Some  of  these 
formulas  provide  an  alcohol  for  burning  purposes 
or  for  use  as  a  special  solvent,  other  represent 
the  reactant  mixture  for  preliminary  manufactur- 
ing processes,  such  as  a  mixture  of  sulfuric  acid 
and  alcohol  for  the  subsequent  production  of 
ether,  while  still  other  formulas,  identical  with 
official  formulas  such  as  iodine  tincture,  soap  lini- 
ment, etc.,  have  been  authorized  and  thus  make 
it  possible  to  have  these  products  manufactured 
from  tax-free  alcohol  at  greatly  reduced  cost.  (See 
also  Alcohol  Rubbing  Compound.)  These  prep- 
arations may  therefore  be  purchased  from  large 
dealers  at  prices  which  are  less  than  the  cost  of 
the  raw  material  if  bought  through  the  usual 
channels  of  trade. 

Under  the  title  Industrial  Methylated  Spirit 
(Spiritus  Methylatus  Industrialis)  the  B.P.  recog- 
nizes a  mixture,  made  by  a  legally  authorized 
methylator,  of  19  volumes  of  95  per  cent  alcohol 
with  1  volume  of  approved  wood  naphtha.  It  is 
of  the  quality  known  as  "66  O.P.  industrial  meth- 
ylated spirits."  Use  of  this  product  is  permitted 
by  the  B.P.  in  the  preparation  of  certain  liniments 
and  test  solutions  and  in  the  manufacture  of  cer- 
tain extracts  and  resins  in  which  none  of  the 
solvent  remains  in  the  finished  product. 

Description. — "Alcohol  is  a  transparent,  color- 
less, mobile,  volatile  liquid.  It  has  a  slight,  char- 
acteristic odor  and  a  burning  taste.  Alcohol  is 
readily  volatilized  even  at  low  temperatures  and 
boils  at  about  78°.  It  is  flammable.  Alcohol  is 
miscible  with  water,  with  ether,  and  with  chloro- 
form. When  Alcohol  is  diluted  with  an  equal 
volume  of  water  the  mixture  is  clear  and  remains 
clear  for  30  minutes  after  cooling  to  10°.  The 
specific  gravity  of  Alcohol  is  not  more  than  0.816 
at  15.56°,  indicating  not  less  than  92.3  per  cent 
by  weight,  or  94.9  per  cent  by  volume,  of 
C2H5OH."  U.S.P.  The  temperature  15.56°  C.  is 
equivalent  to  60°  F.,  the  standard  temperature 
employed  in  stating  concentrations  of  alcohol  in 
per  cent  by  volume. 

Standards  and  Tests. — Acidity. — Not  more 
than  0.9  ml.  of  0.02  N  sodium  hydroxide  is  re- 
quired to  neutralize  50  ml.  of  alcohol,  using 
phenolphthalein  T.S.  as  indicator.  Non-volatile 
residue. — Not  over  1  mg.  from  40  ml.  of  alcohol, 
the  residue  being  dried  at  105°  for  1  hour.  Fusel 
oil  constituents. — No  foreign  odor  is  perceptible 
when  the  alcohol  is  spontaneously  evaporated 
from  a  mixture  of  10  ml.  of  alcohol,  5  ml.  of 
water  and  1  ml.  of  glycerin  placed  on  odorless 
absorbent  paper.  Amyl  alcohol  or  non-volatile, 
carbonizable  substatices,  etc. — No  red  or  brown 
color  is  produced  on  adding  a  few  drops  of  sulfuric 
acid  to  the  nearly  dry  residue  from  the  evapora- 
tion of  25  ml.  of  alcohol  in  a  porcelain  dish,  pro- 
tected from  dust.  Aldehydes  and  other  foreign 
organic  substances. — The  pink  color  produced  by 
the  addition  of  0.1  ml.  of  0.1  TV  potassium  per- 
manganate to  20  ml.  of  alcohol  in  a  thoroughly 
cleansed  glass-stoppered  cylinder,  the  solution 
being  maintained  at  15°,  does  not  entirely  disap- 


36 


Alcohol 


Part   I 


pear  in  5  minutes.  Ketones,  isopropyl  alcohol, 
and  tertiary  butyl  alcohol. — No  precipitate  forms 
within  3  minutes  when  a  mixture  of  1  ml.  of 
alcohol,  3  ml.  of  water  and  10  ml.  of  mercuric 
sulfate  T.S.  is  heated  on  a  bath  of  boiling  water. 
Methanol. — No  violet  color  appears  on  heating 
for  10  minutes  at  60°  a  mixture  of  5  ml.  of  freshly 
prepared  chromotropic  acid  T.S.  and  a  solution 
obtained  when  1  drop  each  of  alcohol,  water, 
dilute  phosphoric  acid  (1  in  20),  and  potassium 
permanganate  solution  (1  in  20)  are  mixed,  al- 
lowed to  stand  1  minute,  treated  with  1  in  20 
sodium  bisulfite  solution  to  discharge  the  per- 
manganate color  and,  if  a  brown  color  remains,  1 
drop  of  the  diluted  phosphoric  acid  added  to  pro- 
duce a  colorless  solution.  U.S.P. 

The  B.P.  specific  gravity  range  is  0.815  to  0.817 
at  15.5/15.5°  and  the  refractive  index,  measured 
at  20°,  may  vary  from  1.3637  to  1.3639. 

Incompatibilities. — The  addition  of  alcohol 
to  aqueous  solutions  may  cause  the  precipitation 
of  alcohol-insoluble  compounds,  such  as  numerous 
inorganic  and  organic  salts,  and  gums  such  as 
acacia.  Oxidizing  agents  may  convert  alcohol  into 
acetaldehyde  and  acetic  acid. 

Uses. — Alcohol  has  a  variety  of  external  and 
internal  uses  in  medicine  and  is  important  in 
pharmacy.  The  local  action  of  alcohol  is  mildly 
irritant,  feebly  anesthetic  and  distinctly  germi- 
cidal and  astringent.  Some  have  contended  that 
the  most  effective  concentration  for  local  anti- 
sepsis is  from  60  to  70  per  cent  by  weight  in 
water;  careful  studies  by  Hatfield  et  al.  (Surgery, 
1943,  13,  931),  in  which  numerous  antiseptics 
were  compared  by  a  modification  of  the  Price 
technic  (v.i.),  showed  that  95  per  cent  ethyl 
alcohol  by  volume  is  superior  in  its  ability  to  kill 
bacteria  on  the  skin  (see  also  Morton,  Ann.  N.  Y. 
Acad.  Sc,  1950,  53,  191).  Such  concentrations 
of  alcohol  will  destroy  most  pathogenic  bacteria 
within  a  relatively  short  time,  but  more  resistant 
spore-bearing  organisms  survive  even  prolonged 
exposure.  Alcohol  is  used  for  general  anesthesia, 
local  destruction  of  nerves  in  lieu  of  surgical 
excision,  as  an  appetizer  and  even  for  parenteral 
or  oral  nutrition.  Its  misuse  creates  vast  social 
and  economic  and  police  problems  and  treatment 
of  intoxication  is  a  frequent  chore. 

Psychomotor  Action. — Alcohol  belongs,  phys- 
iologically as  well  as  chemically,  to  the  group  of 
aliphatic  narcotics.  In  large  doses  it  produces 
coma  analogous  to  ether  anesthesia.  Extensive 
studies  have  permitted  correlation  of  the  con- 
centration of  alcohol  in  blood,  and  also  in  urine 
and  expired  air,  with  action  on  the  central  nervous 
system.  This  information  is  more  of  medicolegal 
than  therapeutic  importance  and  the  figures  must 
be  interpreted  in  the  light  of  knowledge  of  absorp- 
tion and  excretion  in  relation  to  time.  Alcohol  is 
absorbed  rapidly  from  the  gastrointestinal  tract; 
in  the  ordinary  doses  of  alcoholic  beverages  about 
20  per  cent  is  absorbed  by  the  stomach  and  the 
remainder  in  the  intestine.  The  rate  of  absorption 
is  altered  by  the  presence  or  absence  of  food,  as 
well  as  the  type  of  food  present;  protein  as  well 
as  fat  delay  absorption.  Alcohol  is  easily  and 
rapidly  diffusible  and  at  equilibrium  attains  a 
concentration  in  tissues  related  to  the  concentra- 


tion of  water  present  in  the  extracellular  and 
intracellular  compartments.  From  90  to  98  per 
cent  of  ingested  alcohol  is  metabolized  in  the  body 
(v.i.)  and  only  2  to  10  per  cent  is  excreted  as 
such,  chiefly  in  the  urine  and  to  a  lesser  extent  in 
expired  air.  Only  traces  are  found  in  sweat,  milk 
and  bile.  According  to  Ladd  and  Gibson  (Ann. 
hit.  Med.,  1943,  18,  564),  the  concentration  in 
urine  is  about  1.35  times  that  in  arterial  blood; 
it  must  be  remembered  that  a  large  collection  of 
urine  in  the  bladder  represents  the  arterial  blood 
concentration  over  the  period  of  time  this  urine 
was  secreted  by  the  kidneys  and  not  the  blood 
concentration  at  the  time  the  urine  is  voided.  In 
expired  air  the  concentration  is  approximately 
1/2000  of  that  in  arterial  blood.  In  the  obviously 
intoxicated  person,  the  urine  may  contain  as  much 
as  5  Gm.  per  liter  and  the  expired  air  a  few  mg. 
per  liter.  With  ingestion  of  cocktails  containing 
1  ounce  of  whisky  (45  per  cent  alcohol  by  vol- 
ume) the  following  blood  concentrations  may  be 
observed,  on  the  average:  20  minutes  after  the 
first  cocktail,  20  mg.  per  100  ml.;  at  45  minutes, 
having  consumed  a  second  cocktail  at  20  minutes, 
40  mg.  per  100  ml.;  at  60  minutes,  having  con- 
sumed a  third  cocktail  at  40  minutes,  60  mg.  per 
100  ml.;  subsequently  one  ounce  of  whisky  per 
hour  will  maintain  a  blood  concentration  of  ap- 
proximately 60  mg.  per  100  ml.  Without  further 
intake  the  concentration  decreases  at  the  rate  of 
about  10  mg.  per  100  ml.  per  hour.  As  an  ap- 
proximation, 12  ounces  of  beer  or  3  ounces  of 
wine  represent  the  alcohol  content  of  1  ounce  of 
whiskey. 

The  initial  "stimulating"  effect  of  alcohol,  which 
is  actually  a  depression  of  the  inhibitory  activi- 
ties of  the  cerebral  cortex,  is  associated  with  a 
blood  concentration  of  about  30  mg.  per  100  ml. 
(Miles,  /.  Pharmacol.,  1922,  20,  265).  At  this 
stage  performance  may  be  improved  insofar  as 
elimination  of  embarrassment  is  helpful  but  tests 
show  that  there  is  some  loss  in  fine  discrimination. 
At  50  mg.  per  100  ml.,  the  individual  is  not 
"drunk"  but  is  in  the  flippant  stage  of  unbounded 
self-confidence  and  pleasure  with  himself  and  the 
world  in  general.  He  may  neglect  some  social 
niceties  and  knock  over  an  occasional  article.  At 
100  mg.  per  100  ml.,  the  individual  is  "giddy," 
and  at  150  mg.  becomes  clumsy.  There  is  then 
definite  difficulty  in  adjusting  to  the  environment 
and  the  individual  may  be  amused,  ashamed  or 
angry  with  his  incapacity.  Between  150  and  300 
mg.  per  100  ml.  there  is  progressive  deterioration 
of  the  function  of  the  central  nervous  system;  at 
200  mg.  the  person  is  incoordinated  and  uncon- 
trollable and  at  300  mg.  sleepy  and  maudlin;  in 
common  parlance,  he  is  "drunk."  There  is  usually 
emotional  disturbance  from  bitter  tears  to  raucous 
laughter,  progressive  incoordination  resulting  in 
inability  to  dress  or  undress,  and  drowsiness  with 
intermittent  sleep.  With  concentrations  over  300 
mg.,  the  condition  resembles  that  of  the  second 
stage  of  anesthesia  (see  under  Ether) ;  respiration 
is  deep  and  irregular,  vomiting  is  frequent,  even 
when  the  alcohol  has  been  injected  intravenously 
and  there  is  no  gastric  irritation,  persuasion  is 
futile  and  coercion  causes  violent  struggling.  At 
a  concentration  of  400  mg.,   anesthesia  is  pro- 


Part  I 


Alcohol 


37 


found;  at  500  mg.,  the  respiratory  center  is  de- 
pressed and  death  is  likely  if  the  concentration 
remains  above  500  mg.  for  12  hours.  Up  to  the 
anesthetic  concentration,  however,  there  is  little 
effect  on  the  respiratory  or  vasomotor  centers  in 
the  medulla  oblongata.  Newman  (Science,  1949, 
109,  594)  estimated  that  the  maximum  consump- 
tion in  24  hours  short  of  producing  coma  in  a 
70-kilogram  man  was  26^  ounces  of  100  proof 
whisky. 

Circulation. — The  question  of  the  effects  of 
alcohol  on  the  circulation  has  been  the  subject 
of  much  study  and  dispute.  When  administered 
in  moderate  quantity,  it  usually  does  not  produce 
any  marked  change  in  the  blood  pressure.  On  the 
other  hand,  the  rapidity  of  the  flow  of  blood 
through  the  vessels  is  distinctly  accelerated.  This 
combination  of  effects  can  be  most  readily  ex- 
plained by  simultaneous  increase  in  the  cardiac 
action  and  dilatation  of  the  blood  vessels.  In- 
creased muscular  activity  accounts  for  some  in- 
crease in  circulation.  Grollman  (Quart.  J.  Stud. 
Alcohol,  1942,  3,  5)  believes  the  vasodilatation 
is  due  to  the  depressant  effect  of  alcohol  on  the 
vasomotor  centers  in  the  brain.  Further,  he  attrib- 
uted much  of  what  effect  alcohol  does  have  on 
the  circulation  to  reflex  activity  from  the  mouth 
and  to  psychic  components. 

The  widening  of  the  blood  vessels  is  most 
noticeable  in  the  vessels  of  the  skin.  Horwitz  et  al. 
(Am.  J.  Med.  Sc,  1949,  218,  669)  compared 
the  efficacy  of  various  vasodilators  and  found  that 
a  dose  of  60  to  100  ml.  of  whisky  was  most  effec- 
tive in  increasing  blood  flow  to  the  fingers  and 
to  a  lesser  extent  to  the  toes.  Except  for  the 
habituating  action  of  alcohol  it  is  an  effective 
symptomatic  remedy  in  Buerger's  disease.  It  may 
also  be  useful  in  cases  of  embolism  of  the  smaller 
peripheral  arteries.  With  blood  concentrations 
which  permit  ambulation  there  is  little  effect  on 
the  heart.  McDowall  (/.  Pharmacol.,  1925,  25, 
289)  found  that  large  doses  of  alcohol  cause  a 
marked  fall  in  the  venous  pressure  and  believes 
that  many  of  the  clinical  benefits  which  have  fol- 
lowed the  use  of  alcohol  can  be  attributed  to  a 
dilatation  of  the  veins.  Grollman  points  to  its 
capacity  to  allay  worry  and  anxiety  as  the  most 
valuable  effect  of  alcohol  on  the  circulation,  the 
sedative  action  being  paramount. 

In  angina  pectoris  alcoholic  beverages  have  a 
long-established  reputation.  Stearns  et  al.  (New 
Eng.  J.  Med.,  1946,  234,  578)  found  that  alcohol 
decreased  the  duration  of  the  symptoms  but  not 
of  the  objective  findings  as  a  result  of  the  2 -step 
exercise  test  in  cases  of  coronary  insufficiency. 
In  an  attack  of  angina  pectoris,  nitroglycerin  is 
certainly  preferred,  since  the  action  of  alcohol  is 
that  of  a  sedative  rather  than  a  coronary  dilator 
(Russek  et  al.,  J.A.M.A.,  1953,  153,  207).  Pro- 
phylactic use  of  wine  at  the  end  of  the  day's  work 
seems  rational.  Studies  of  cerebral  blood  flow  by 
Battey  et  al.  (ibid.,  1953,  152,  6)  found  that 
alcohol  is  not  an  effective  cerebral  vasodilator; 
in  humans,  at  a  blood  alcohol  concentration  of 
68  mg.  per  100  ml,  there  was  no  effect  on  cerebral 
blood  flow  or  oxygen  consumption,  but  at  320  mg. 
per  100  ml.  the  cerebral  flow  was  increased  while 
the  oxygen  consumption  was  decreased. 


Metabolism. — When  a  moderate  quantity  of 
alcohol  is  ingested,  from  90  to  95  per  cent  is  com- 
pletely oxidized  in  the  system,  only  traces  of  the 
drug  being  recoverable  from  either  the  urine  or 
breath.  The  oxidation  of  this  hydrocarbon  yields 
energy  amounting  to  7  Calories  per  gram,  the 
oxidation  products  being  carbon  dioxide  and  water. 
The  experiments  of  Atwater  and  Benedict  (Mem- 
oirs of  the  National  Academy  of  Science,  1902, 
7),  of  Mitchell  (/.  Nutrition,  1935,  10,  311)  and 
of  many  others,  seem  to  prove  that  small  amounts 
of  alcohol  are  entirely  capable  of  replacing,  to  a 
considerable  degree,  a  portion  of  the  carbohydrate 
foodstuffs. 

The  metabolism  of  alcohol  is  initiated  in  the 
liver  by  conversion  to  acetaldehyde  and  thence 
to  acetic  acid  which  may  be  metabolized  in  many 
tissues  in  the  manner  of  degradation  products  of 
carbohydrate.  The  respiratory  quotient  of  alcohol 
is  0.667,  and  its  combustion  may  spare  that  of 
carbohydrate,  fat  and  protein.  Alcohol  cannot  be 
stored  in  the  body  and  in  the  absence  of  food  it 
will  not  form  liver  glycogen.  Goldfarb  et  al. 
(J.  Clin.  Inv.,  1939,  18,  581)  found  that  simul- 
taneous administration  of  dextrose  and  insulin 
increased  the  rate  of  oxidation  of  alcohol;  this 
may  prove  helpful  in  treatment  of  severe  intoxi- 
cation. Although  the  rate  of  metabolism  of  alcohol 
varies  with  many  circumstances,  the  average  may 
be  about  10  Gm.  per  hour.  The  caloric  sig- 
nificance of  alcohol  may  be  illustrated  by  noting 
that  the  ingestion  of  1  pint  of  whisky  in  24  hours 
could  result  in  the  combustion  of  170  Gm.  of 
alcohol  and  the  production  of  1,200  Calories, 
which  represents  the  basal  caloric  requirement  of 
a  good-sized  man.  If  his  food  consumption  de- 
creases accordingly,  avitaminosis  and  other  evi- 
dences of  malnutrition  result;  if  food  consump- 
tion continues,  obesity  results.  Usual  concentra- 
tions do  not  seem  to  effect  liver  function,  but 
Newman  et  al.  (J.  Pharmacol.,  1940,  168,  194) 
found  decreased  liver  glycogen,  increased  blood 
lactic  acid  and  decreased  hepatic  oxygen  con- 
sumption following  high  concentrations  of  alcohol 
in  the  blood.  A  low  normal  sulfobromophthalein 
clearance  was  reported  in  chronic  alcoholics  with- 
out obvious  liver  disease  (Goodman  and  Kings- 
ley,  J.A.M.A.,  1953,  153,  462). 

Gastrointestinal. — Alcohol  has  a  marked  in- 
fluence on  gastric  and  probably  also  intestinal 
digestion.  As  a  carminative  in  flatulent  dyspepsia, 
alcoholic  beverages  or  alcoholic  solutions  of  essen- 
tial oils  (tinctures)  are  commonly  used  with 
symptomatic  benefit. 

Dilute  alcohol  solutions  stimulate  gastric  secre- 
tion; 50  ml.  of  7  per  cent  alcohol  is  commonly 
used  as  a  test  meal  in  lieu  of  the  classical  tea-and- 
toast  meal  and  has  the  advantage  of  containing 
no  particulate  matter  to  block  the  aspirating  tube. 
Roth  et  al.  (J.A.M.A.,  1944,  126,  814)  reported 
that  the  alcohol  test  meal  caused  a  greater  rise 
in  free  hydrochloric  acid  in  patients  with  peptic 
ulcer  than  in  normal  persons.  Concentrations  up 
to  10  per  cent  produce  a  gastric  juice  rich  in 
hydrochloric  acid  although  poor  in  pepsin  (Bloom- 
field  and  Keefer,  J.  Clin.  Inv.,  1928,  5,  295). 
Concentrations  of  20  to  40  per  cent  alcohol  or 
more  cause  inflammation  of  the  gastric  mucosa 


38 


Alcohol 


Part  I 


(Beazell  and  Ivy,  Quart.  J.  Stud.  Alcohol,  1940, 
1,  45).  After  section  of  the  vagi  or  their  paralysis 
by  atropine  this  increase  in  the  digestive  secre- 
tions does  not  occur.  (For  further  information 
on  the  effects  of  alcohol  on  digestion,  see  Gray, 
Am.  J.  Physiol,  1937,  120,  657.)  It  has  been 
shown  by  Greenberg,  Lolli,  and  Rubin  {Quart.  J. 
Stud.  Alcohol,  1942,  3,  371)  that  intravenously 
administered  alcohol  delays  the  emptying  time 
of  the  stomach. 

Skin. — Alcohol  is  widely  used  for  application 
to  the  skin.  It  serves  as  an  irritant,  an  anhidrotic. 
and  an  astringent  by  virtue  of  its  precipitation  of 
cellular  protein,  thus  being  useful  in  the  hygienic 
care  of  the  skin  in  bed-ridden  patients  and  the 
prevention  of  decubitus  ulcers.  Its  cooling  quality 
on  evaporation  is  well  known  in  the  nursing  care 
of  febrile  patients.  It  may  be  used  to  remove 
phenol,  poison  ivy,  etc.,  from  the  skin.  There  is 
no  more  widely  used  antiseptic  for  the  skin  in 
preparation  for  surgical  procedures,  as  well  as  in 
the  disinfection  of  surgical  instruments.  Price 
(Arch.  Surg.,  1950,  60,  492)  reported  that  a 
2-minute  washing  of  the  surgeon's  hands  in  70  to 
95  per  cent  alcohol  decreased  the  surviving  bac- 
terial flora  to  less  than  10  per  cent.  Lesser  con- 
centrations were  less  effective.  Some  bacterial 
spores  are  resistant  to  alcohol.  Heat  sterilization 
is  necessary  for  surgical  instruments.  Further- 
more, storage  in  alcohol  results  in  rusting  of  steel 
instruments.  Price  (J.A.M.A.,  1944,  124,  189) 
recommended  its  use  locally  for  the  treatment  of 
furunculosis.  For  intractable  pulmonary  edema, 
Gootnick  et  al.  (New  Eng.  J.  Med.,  1951,  245, 
842)  and  Luisada  et  al.  (Circulation,  1952,  5, 
363)  nebuilized  50  per  cent  alcohol  and  caused 
its  inhalation  with  oxygen  pressure  in  a  meter 
mask.  The  alcohol  has  an  antifoaming  action, 
causing  the  fine  bubbles  in  the  smaller  bronchi 
to  collapse  and  permit  entry  of  the  oxygen. 

Xerve  Block. — Alcohol  is  used  by  injection 
for  intractable  pain,  as  in  trigeminal  neuralgia 
(tic  douloureux)  (Sweet,  J.A.M.A.,  1950,  142, 
392),  angina  pectoris  (Levy  and  Moore,  J. A.M. A., 
1941,  116,  2563),  inoperable  cancer  of  the  pelvis, 
and  in  sciatica. 

In  the  management  of  intractable  pain  in  the 
pelvis  or  legs,  0.75  ml.  of  absolute  or  95  per  cent 
alcohol  is  injected  slowly  over  a  period  of  2  min- 
utes through  a  lumbar  puncture  needle  in  the 
fourth  lumbar  interspace  with  the  patient  lying 
on  the  side  opposite  to  that  with  the  most  pain. 
The  patient  must  remain  in  this  lateral  recumbent 
position  for  2  hours.  The  specific  gravity  of  the 
alcohol  is  less  than  that  of  the  spinal  fluid  and 
the  alcohol  in  this  lateral  recumbent  position 
rises  into  contact  with  the  posterior  spinal  roots. 
Spinal  fluid  should  not  be  withdrawn  to  mix  with 
the  alcohol  in  the  syringe.  If  needed  the  injection 
may  be  repeated  for  the  other  side  a  week  or  two 
later.  Considerable  neuritic  pain  may  follow  this 
injection  for  1  to  2  weeks  and  in  some  instances 
the  motor  nerves  may  be  damaged  by  the  alcohol. 
This  procedure  is  indicated  only  for  severe  pain 
in  metastatic  carcinoma  or  other  hopeless  condi- 
tion (Bonica,  /.  Michigan  M.  Soc,  1953,  52, 
284)  because  of  the  arachnoiditis,  and  damage  to 
the  spinal  cord  it  produces. 


Stellar  (Arch.  Neurol.  Psychiat.,  1953,  69, 
343)  used  subarachnoid  injections  of  alcohol  to 
relieve  spasticity  and  contractures  in  paraplegic 
patients. 

Retrobulbar  injections  of  alcohol  for  painful 
eyes  which  cannot  be  enucleated  surgically  for 
some  reason  gave  relief  for  several  months  and 
did  not  permanently  destroy  remaining  visual 
ability  (Maumenee,  Am.  J.  Ophth.,  1949,  32, 
1502). 

In  prolonged,  severe  pain,  alcohol  injections 
have  been  employed  to  destroy  temporarily  the 
peripheral  nerve  from  the  involved  area.  This 
has  been  done  with  the  intercostal  nerves  in  in- 
stances of  tuberculous  or  other  chronic  form  of 
pleurisy.  Klein  (Wien.  klin.  Wchnschr.,  1949,  99, 
512)  reported  successful  use  of  alcohol  injections 
of  the  sympathetic  nerve  chain  at  the  fifth  and 
tenth  thoracic  vertebral  levels  in  lieu  of  sympa- 
thectomy in  cases  of  severe  hypertension. 

For  intractable  pruritus  vulvae,  Wilson  (West. 
J.  Surg.  Obst.  Gynec,  1949,  57,  406)  made  multi- 
ple subcutaneous  injections  of  0.1  to  0.25  ml., 
spaced  about  1  to  2  cm.  apart,  with  relief  in  about 
half  of  the  cases. 

Anesthesia. — Intravenous  alcohol  anesthesia 
was  reported  by  Verkhovskaya  (Am.  Rev.  Soviet 
Med.,  1945,  2,  260).  His  patients  in  an  evacua- 
tion hospital  were  prepared  as  for  ether  anesthesia. 
The  solution  used  is  one  part  95  per  cent  alcohol 
with  two  parts  of  5  per  cent  dextrose  solution, 
the  average  amount  for  narcosis  being  2  to  2.5  ml. 
per  Kg.  body  weight.  For  example,  a  60  Kg. 
patient  needs  120  ml.  of  alcohol  and  240  ml.  of 
dextrose  solution.  The  infusion  is  given  slowly 
over  15  or  20  minutes  until  the  patient  sleeps. 
After  deep  anesthesia  is  present  the  vein  is  flushed 
with  30  to  40  ml.  of  normal  saline  to  prevent 
thrombo-phlebitis.  Sleep  lasts  two  to  five  hours. 
The  dose  is  more  difficult  to  regulate  than  with 
ether  by  inhalation  and  the  reflexes  are  less  well 
depressed  than  with  ether.  The  prolonged  re- 
covery period  is  often  undesirable. 

Child  (Ar.  Y.  State  J.  Med.,  1951,  51,  1521) 
found  this  solution,  with  added  vitamins,  useful 
in  the  management  of  the  withdrawal  syndrome 
of  opium  addicts. 

Chapman  and  Williams  (Am.  J.  Obst.  Gyn., 
1951,  61,  676)  used  7.5  per  cent  alcohol  in  5  per 
cent  dextrose  injection  intravenously  for  ob- 
stetrical analgesia,  along  with  otherwise  ineffective 
doses  of  meperidine,  successfully  except  for  vomit- 
ing in  some  cases  and  the  difficulty  of  keeping 
the  needle  in  the  vein.  Determinations  of  alcohol 
in  the  cord  blood  showed  that  alcohol  reached 
the  fetus,  but  depression  of  respiration  was  not 
observed. 

In  status  asthmaticus  in  children,  5  per  cent 
ethyl  alcohol  in  5  per  cent  dextrose  in  isotonic 
sodium  chloride  solution  or  distilled  water  for 
injection  has  been  employed  in  a  dose  of  40  ml. 
per  kilogram  of  body  weight;  the  first  80  to  100 
ml.  is  given  in  a  period  of  10  minutes  and  the 
remainder  of  the  dose  at  a  rate  of  2  drops  per 
kilogram  per  minute  (Bacal  and  Pedvis,  Can. 
Med.  Assoc.  J.,  1948,  59,  410).  In  the  control  of 
intractable  pain,  5  or  10  per  cent  alcohol  in  5  per 
cent  dextrose  may  be  given  intravenously;  relief 


Part  I 


Alcohol 


39 


is  transient  and  the  resulting  inebriation  may  be 
unpleasant. 

For  postspinal-puncture  headache,  which  is 
often  totally  disabling  and  resistant  to  therapy, 
Deutsch  (Anesth.,  1952,  13,  496)  gave  1  liter  of 
5  per  cent  alcohol  in  5  per  cent  dextrose  injection 
intravenously  over  a  period  of  4  hours  with  relief 
in  10  of  15  cases. 

Parenteral  Nutrition. — Rasmussen  (Jackson 
Clin.  Bull.,  1945,  7,  45)  recommended  intravenous 
alcohol  as  supportive  treatment  postoperatively, 
administering  1  to  3  liters  of  5  to  10  per  cent 
solution  in  5  per  cent  dextrose  and  saline  solution. 
Alcohol  may  be  administered  intravenously  to 
adults  at  a  rate  up  to  15  ml.  per  hour  without 
causing  significant  inebriation.  In  addition  to  some 
sedative  action,  it  has  nutritional  value  in  the  fre- 
quently malnourished  postoperative  case  (Karp 
and  Sokol,  J.A.M.A.,  1951,  146,  21).  Pending 
the  availability  of  stable  fat  emulsions  for  in- 
travenous injection  to  supply  calories  in  sufficient 
quantity  to  spare  protein  tissue  from  combustion 
for  the  daily  caloric  requirement  such  an  alcohol- 
saline-dextrose  mixture  with  5  per  cent  protein 
hydrolysate  is  useful  (Rice  et  al.,  J. -Lancet,  1948, 
78,  91)  ;  the  alcohol  provides  7  Calories  per  gram. 
In  malnourished  individuals,  it  is  important  to 
add  therapeutic  doses  of  the  B-vitamins  to  this 
solution  to  avoid  precipitation  of  the  enceph- 
alopathy of  Wernicke  with  the  large  dose  of 
carbohydrate. 

Stimulant. — As  a  circulatory  stimulant  there 
is  no  doubt  that  in  the  past  too  much  confidence 
has  been  placed  in  alcohol.  Nevertheless,  if  used 
circumspectly,  it  is  often  of  value.  Myers 
(/.  Pharmacol,  1933,  49,  483),  in  studying  the 
treatment  of  the  shock  produced  by  diphtheria 
toxin,  found  that  alcohol  was  the  only  drug  of 
those  he  tested  which  caused  a  definite  improve- 
ment in  the  circulation.  It  is  used  especially  when 
it  is  desired  to  tide  the  patient  over  for  a  limited 
period  of  time.  It  must  never  be  forgotten  that 
large  doses  are  depressant.  While  a  small  amount 
of  alcohol  may  prove  useful  in  cases  of  snake  bite, 
it  is  no  exaggeration  to  say  that  the  injudicious 
exhibition  of  this  drug  has  been  responsible  for 
many  deaths  after  rattlesnake  bites,  where  the 
specific  antivenin  would  have  been  life-saving. 
In  the  circulatory  failure  due  to  anesthetics  it 
should  be  sedulously  avoided;  on  account  of  its 
close  chemical  relation  to  both  ether  and  chloro- 
form it  acts  as  a  synergist  rather  than  an  antag- 
onist to  these  poisons.  The  use  of  alcohol  in 
infectious  fevers,  especially  typhoid  fever,  in- 
volves a  large  number  of  factors  concerning  some 
of  which  we  have  at  present  no  definite  knowledge. 
The  impairment  of  digestion,  which  is  so  uni- 
versal an  accompaniment  of  these  diseases,  sug- 
gests the  use  of  alcohol  both  as  a  stimulant  to 
gastric  secretion  and  as  an  accessory  food.  While 
febrile  patients  are  capable  of  burning  up  larger 
quantities  of  alcohol  than  normal  individuals,  if 
given  too  freely  the  unoxidized  alcohol  circulat- 
ing in  the  blood  may  prove  injurious.  An  alco- 
holic odor  to  the  breath  is  generally  a  sign  that 
the  patient  is  receiving  more  than  he  can  oxidize. 
Many  believe  that  the  mild  narcotic  action  of 


alcohol  is  also  of  service  in  preserving  the  vitality 
in  these  adynamic  states. 

Taken  internally,  alcohol  tends  to  increase  the 
sweat  by  dilating  the  vessels  of  the  skin  and  is 
frequently  used  as  an  aid  to  more  powerful 
diaphoretic  measures  in  the  abortion  of  mild  in- 
fections, such  as  acute  coryza. 

In  dysmenorrhea,  alcoholic  beverages  are  often 
an  effective  analgesic  but  the  general  action  is 
undesirable  in  this  recurrent  condition. 

In  insomnia,  particularly  in  older  people,  an 
alcoholic  beverage  at  bedtime  may  be  most  effec- 
tive in  bringing  relaxation  and  sleep;  for  this 
purpose  the  dose  should  not  exceed  10  to  20  ml. 
of  whisky,  lest  excitement  rather  than  sedation  be 
produced.  Alcohol  relaxes  athetosis  but  it  is  hardly 
possible  to  use  it  in  the  treatment  of  this  chronic 
disorder. 

Raw  alcohol  is  rarely  used  internally,  prefer- 
ence being  shown  for  one  of  the  alcoholic  bever- 
ages, such  as  whisky,  brandy,  or  wine. 

Pharmaceutical  Uses. — Various  strengths  of 
alcohol  are  used  in  pharmacy,  as  for  preservation 
of  a  variety  of  medicinals,  extraction  of  active 
principles  of  crude  drugs,  and  for  dissolving  sub- 
stances which  are  more  soluble  in  hydroalcoholic 
media  than  they  are  in  water.  IYJ 

Toxicology. — The  symptoms  of  acute  alcohol 
poisoning  are  unfortunately  so  widely  known  that 
detailed  description  is  unnecessary,  but  alcohol 
poisoning  is  of  great  importance,  not  alone  be- 
cause of  the  frequency  of  serious  results,  but  be- 
cause of  the  similarity  of  its  symptoms  with  those 
of  certain  diseases  or  other  narcotic  poisons.  The 
odor  of  paraldehyde  on  the  breath  may  be  mis- 
taken for  alcohol.  Barbiturate  poisoning,  skull 
fracture,  cerebral  hemorrhage  or  schizophrenia 
may  simulate  alcoholism.  The  important  diag- 
nostic symptoms  are  the  characteristic  odor  on 
the  breath  and  the  peculiar  maudlin  mentality,  if 
the  patient  can  be  aroused.  Nystagmus,  clumsy 
performance  of  coordinated  movements,  such  as 
walking  a  straight  line,  and  impaired  perception 
of  fine  differences  are  characteristic.  In  the  coma- 
tose state  the  pupils  are  usually  somewhat  dilated, 
the  face  is  flushed,  the  skin  is  cold  and  moist,  the 
pulse  is  rapid  and  the  breathing  noisy  and  re- 
duced in  frequency.  The  fatal  dose  of  whisky 
requires  the  ingestion  of  1  quart  within  a  few 
minutes,  which  seldom  occurs  because  of  incoordi- 
nation and  pylorospasm. 

The  treatment  of  alcohol  poisoning  consists  in 
the  immediate  evacuation  of  the  stomach,  main- 
tenance of  body  temperature  by  use  of  external 
heat,  and  use  of  respiratory  stimulants,  notably 
caffeine  and  sodium  benzoate  or  enemas  of  strong 
coffee.  Inhalation  of  aromatic  ammonia  spirit 
may  arouse  temporarily.  Carbon  dioxide  (5  per 
cent)  and  oxygen  (95  per  cent)  inhalations  are 
required  in  profound  coma.  Apomorphine  solu- 
tion is  often  injected  but  in  an  alcoholic  patient 
it  may  produce  still  further  depression  rather  than 
initiating  vomiting.  Ephedrine  or  amphetamine 
may  be  helpful. 

Habitual  alcoholism  is  a  major  health  and  eco- 
nomic problem.  More  is  spent  annually  on  alco- 
holic beverages  than  on  health.  Block  (GP,  Sept. 
1952)  estimated  the  cost  of  the  effects  of  alco- 


40 


Alcohol 


Part   I 


holism  to  exceed  a  half  billion  dollars  yearly;  20 
million  by  private  and  another  20  million  by 
public  agencies  in  the  care  of  the  families  of 
problem  drinkers,  30  million  for  the  care  of  alco- 
holics in  mental  hospitals,  25  million  for  the  care 
of  alcoholic  prisoners  in  jails,  125  million  expense 
of  preventable  accidents  due  to  alcohol,  and  over 
a  half  billion  in  loss  of  productivity  in  industry 
due  to  alcoholism.  About  half  of  all  chronic  alco- 
holics have  an  underlying  mental  disorder.  The 
other  half,  commencing  as  "social  drinkers," 
enjoy  the  escape  from  the  frustrations  of  life  and 
by  virtue  of  frequent  excessive  indulgence  become 
less  able  to  cope  with  their  problems  and  sink  into 
the  results  of  chronic  alcoholism.  Gastritis  is  not 
infrequent.  Alcoholism  is  present  in  most  cases 
of  cirrhosis  of  the  liver  but  the  relation  is  not  one 
of  a  toxic  effect  of  alcohol  on  the  liver.  Malnutri- 
tion secondary  to  a  failure  to  eat  an  adequate 
diet  is  important.  The  glucose  tolerance  may  be 
altered  (see  Voegtlin,  Quart.  J.  Stud.  Alcohol, 
1943,  4,  163).  Dewan  (Am.  J.  Psychiat.,  1943, 
99,  565)  indicates  that  riboflavin  and  niacin  are 
components  of  the  oxidation  mechanism  of  alcohol 
within  the  brain  substance,  this  mechanism  acting 
as  a  hydrogen  carrier  between  reduced  diphospho- 
pyridine  nucleotide  and  the  cytochrome  system. 
Spies  and  Aring  (J. A.M. A.,  1938,  110,  1081) 
snowed  that  "alcoholic  polyneuritis"  could  be 
cured  by  correcting  the  malnutrition  without  dis- 
continuing the  alcohol  intake.  Emaciation  and 
general  ill  health  in  the  alcoholic  seems  to  be 
due  to  malnutrition.  The  red  nose  and  the  acne- 
form  skin  lesions  may  be  related  to  ariboflavinosis. 
Korsakoff's  psychosis  described  in  chronic  alco- 
holics resembles  the  mental  aberration  seen  in 
pellagra.  Wernicke's  syndrome  is  related  to  a 
deficiency  of  vitamin  B. 

Figueroa  et  al.  (J.  Clin.  Nutrition,  1953,  1, 
179)  comment  on  the  low  incidence  of  frank 
avitaminosis  in  chronic  alcoholics  at  the  present 
time  in  contrast  to  the  higher  incidence  in  the 
past. 

Delirium  tremens  is  characterized  by  an  acute 
panic,  excitement  and  fear,  visual  and  auditory 
hallucinations  and  marked  exhaustion.  It  may  be 
precipitated  in  the  chronic  alcoholic  by  inter- 
current disease,  sudden  withdrawal  of  alcohol  or 
an  increased  consumption  of  alcohol.  Cerebral 
edema  is  often  present  and  may  cause  death. 
Alcohol  tends  to  cause  an  increase  in  extracellular 
fluid.  Alcoholics  are  seriously  ill  and  require  care- 
ful supportive  therapy.  Much  folklore  concerns 
the  increased  tolerance  of  the  chronic  drinker  to 
alcohol  but  the  increased  consumption  never  ap- 
proaches the  magnitude  of  the  morphine  addict. 
Schweisheimer  {Deutsch.  Arch.  f.  klin.  Med., 
1912-3.  109,  271)  showed  that  the  non-drinker 
reacted  much  more  violently  to  a  given  concen- 
tration of  alcohol  in  the  blood  than  did  the 
habitual  consumer  of  alcoholic  beverages.  Animal 
studies  by  Newman  and  Lehman  (/.  Pharmacol., 
1938,  62,  301)  showed  that  symptoms  appeared 
in  habituated  animals  only  at  higher  concentra- 
tions in  the  blood  than  in  previously  unexposed 
animals;  since  the  brain  in  these  habituated  ani- 
mals was  equally  permeable  to  the  alcohol,  it  was 
suggested  that  the  cells  had  become  resistant  to 


the  effects  of  the  lower  concentration.  At  the 
most  this  increased  tolerance  is  not  more  than 
2  or  3  times  that  of  the  unexposed  individual. 
The  resistance  of  chronic  alcoholics  to  the  related 
anesthetics  such  as  ether  and  chloroform  is  com- 
patible with  such  an  explanation. 

The  management  of  the  chronic  alcoholic  is 
initially  protective  and  supportive  until  malnutri- 
tion can  be  corrected  and  health  restored.  Defini- 
tive treatment  is  psychiatric  in  nature  and  has 
been  most  successful  under  the  auspices  of  such 
organizations  as  Alcoholics  Anonymous,  in  which 
group  psychotherapy  and  occupational  therapy 
are  conducted  by  individuals  who  themselves 
have  recovered  from  chronic  alcoholism.  This 
voluntary  approach  has  been  the  most  successful, 
particularly  in  the  older  individual  with  previous 
skills  and  with  family  obligations.  It  is  unfortu- 
nate that  the  individual  must  often  be  hurt  so 
badly  before  he  voluntarily  associates  himself 
with  such  a  group,  but  the  desire  to  reform  is 
essential  to  the  discontinuance  of  alcohol.  As 
already  noted  delirium  tremens  requires  expert 
medical  care.  The  former  practice  of  lumbar 
puncture  to  withdraw  spinal  fluid  to  relieve  pres- 
sure resulted  in  many  fatalities,  perhaps  as  a  re- 
sult of  herniation  of  the  brain  stem  through  the 
foramen  magnum;  the  use  of  magnesium  sulfate 
by  mouth  or,  in  emergencies,  50  per  cent  dextrose 
intravenously  is  effective  and  safer.  Smith 
(J.A.M.A.,  1953,  152,  384)  recommended  the 
following  regimen:  hospitalize  under  careful  nurs- 
ing care;  inject  1  liter  of  5  per  cent  dextrose  in 
isotonic  sodium  chloride  solution  (for  injection) 
containing  500  mg.  ascorbic  acid,  200  mg.  thia- 
mine hydrochloride  and  100  mg.  nicotinamide 
intravenously  and  repeat  in  12  hours;  give  paral- 
dehyde 10  to  16  ml.  or  chloral  hydrate  1  to  2 
Gm.  by  mouth  as  often  as  needed  to  control 
delirium  and  mephobarbital  200  mg.  four  times 
daily  by  mouth.  Feldman  and  Zucker  (J.A.M.A., 
1953,  153,  895)  confirmed  the  value  of  adrenal 
cortical  extract  to  shorten  convalescence  (see 
under  Adrenal  Cortex  Injection).  Under  sanato- 
rium control,  the  use  of  alcoholic  beverages  along 
with  nauseants,  such  as  ipecac  or  apomorphine 
(Feldman,  Praxis,  1952,  41,  871),  may  be  useful 
but  cannot  substitute  for  the  determination  of  the 
individual  to  discontinue  use  of  alcohol  com- 
pletely. The  use  of  tetraethylthiuram  disulfide 
(see  in  Part  II),  which  causes  intense  discomfort 
if  alcohol  is  ingested,  may  be  useful  in  the  same 
way  as  the  nauseants. 

Because  of  the  medicolegal  importance  in  auto- 
mobile accidents  resulting  from  driving  while 
intoxicated,  and  also  in  the  investigation  of  violent 
deaths  (Wilentz,  Am.  Pract.  Dig.  Treat.,  1953,  4, 
21),  tests  of  alcohol  levels  in  blood  and  urine  are 
of  great  importance.  A  useful  quantitative  test  is 
described  in  Levinson  and  MacFate's  Clinical 
Laboratory  Diagnosis,  4th  Edition,  1951;  in  this 
test  alcohol  is  quantitatively  oxidized  to  acetic 
acid  by  a  standard  potassium  dichromate  solution 
used  in  excess,  the  excess  of  the  latter  being  de- 
termined through  liberation  of  iodine  from  potas- 
sium iodide  and  titration  with  standard  sodium 
thiosulfate  solution.  The  National  Safety  Coun- 
cil (Progress  Report  of  the  Committee  on  Tests 


Part  I 


Alcohol,   Diluted  41 


for  Intoxication  of  the  Street  and  Highway  Traffic 
Section,  1937)  recommended  that  a  blood  concen- 
tration of  more  than  0.15  per  cent  is  conclusive 
evidence  of  intoxication;  levels  of  0.05  per  cent 
to  0.15  per  cent  may  be  associated  with  mild 
intoxication,  which  must  be  evaluated  by  tests 
of  psychomotor  performance;  if  the  level  is  less 
than  0.05  per  cent  the  driver  should  not  be 
prosecuted  (Newman,  /.  Clin.  Psychopath., 
1946-7,  8,  83).  Alcohol  should  not  be  applied  to 
the  skin  before  taking  blood  samples.  Sodium 
fluoride  (500  mg.  for  a  blood  specimen  of  3  to  6 
ml.)  will  serve  as  an  anticoagulant  and  preserva- 
tive of  the  alcohol  for  many  hours  if  analysis 
must  be  delayed.  An  alcoholmeter  for  simple  and 
almost  automatic  estimation  of  alcohol  in  expired 
air  was  developed  by  Greenberg  and  Keator 
(Quart.  J.  Stud.  Alcohol,  1941-2,  2,  57)  for  use 
by  trained,  nonmedical  personnel  in  police  de- 
partments. In  this  apparatus  the  alcohol  in  the 
breath  reacts  with  pentoxide  and  in  turn  pro- 
duces a  starch-iodine  blue  color  which  is  recorded 
by  a  photoelectric  cell. 

Storage. — Preserve  "in  tight  containers,  re- 
mote from  fire."  U.S.P. 

DEHYDRATED  ALCOHOL.     N.F.  (LP.) 

Dehydrated  Ethanol,  "Absolute  Alcohol"   [Alcohol 
Dehydratum] 

"Dehydrated  Alcohol  contains  not  less  than 
99  per  cent  by  weight  of  C2H6O."  N.F.  The  LP. 
Absolute  Ethanol  is  ethyl  alcohol  with  not  more 
than  2  per  cent  w/w  of  water;  not  less  than  98.8 
per  cent  v/v,  corresponding  to  not  less  than  98.1 
per  cent  w/w,  of  C2H5OH  is  required. 

Alcohol  Absolutus;  Alcohol  Ethylicum;  Spiritus  Abso- 
lutus.  Fr.  Alcool  ethylique;  Ethanol;  Alcool  absolu;  Alcool 
a  cent  degres  centesimaux.  Ger.  Absoluter  Alkohol.  It. 
Alcool  etilico  assoluto.  Sp.  Alcohol  absoluto;  Alcohol 
deshidratado. 

The  term  "absolute  alcohol"  is  properly  applied 
only  to  100  per  cent  C2H5OH;  the  correct  desig- 
nation for  a  liquid  containing  over  99  per  cent, 
but  less  than  100  per  cent,  of  C2H5OH,  is  de- 
hydrated alcohol. 

As  mentioned  previously,  the  maximum  concen- 
tration of  C2H5OH  obtainable  by  the  regular 
methods  of  fractional  distillation  is  95.57  per 
cent,  corresponding  to  the  composition  of  the 
constant-boiling  mixture  of  alcohol  and  water. 
By  azeotropic  distillation  in  which  a  third  compo- 
nent, such  as  benzene,  is  present,  it  is  possible  to 
prepare  even  absolute  alcohol.  The  process  de- 
pends on  the  fact  that  when  a  mixture  of  ordinary 
alcohol  and  benzene  is  distilled  the  initial  frac- 
tion, passing  over  at  64.8°,  contains  benzene, 
water  and  alcohol;  the  second  fraction,  distilling 
at  68.2°,  is  composed  of  benzene  and  alcohol;  the 
third,  boiling  at  78.3°,  is  absolute  alcohol.  This  is 
the  commercial  process  for  preparing  dehydrated 
alcohol.  A  similar  use  of  ether  as  an  entraining 
agent  has  been  proposed. 

Prior  to  the  use  of  the  azeotropic  distillation 
process,  dehydrated  alcohol  was  prepared  by  add- 
ing to  alcohol  various  substances  which  possess 
an  affinity  for  water.  The  British  Pharmacopoeia 
of  1895  directed  that  alcohol  be  kept  in  contact 
with  anhydrous  potassium  carbonate  during  24 


hours,  decanted,  then  allowed  to  stand  in  contact 
with  fused  calcium  chloride  for  a  like  period,  and 
finally  distilled  from  the  latter.  Other  drying 
agents  which  have  been  used,  and  still  are  em- 
ployed in  laboratory  preparation  of  dehydrated 
alcohol,  are  freshly  calcined  lime,  anhydrous 
potassium  and  sodium  acetates,  barium  oxide,  and 
metallic  calcium,  which  last  reacts  with  water  to 
form   calcium  hydroxide. 

Description  and  Tests. — "Dehydrated  Al- 
cohol is  a  transparent,  colorless,  mobile,  and  vola- 
tile liquid,  having  a  characteristic  odor,  and  a 
burning  taste.  It  is  hygroscopic  and  flammable. 
Dehydrated  Alcohol  is  readily  volatilized  even  at 
low  temperatures  and  boils  at  about  78°.  Dehy- 
drated Alcohol  is  miscible  with  water  without  any 
trace  of  cloudiness.  It  is  also  miscible  with  ether 
and  with  chloroform.  The  specific  gravity  of 
Dehydrated  Alcohol  is  not  more  than  0.798  at 
15.56°  (the  U.  S.  Government  standard  tempera- 
ture for  Alcohol)."  N.F. 

The  N.F.  prescribes  the  same  tests  for  this 
liquid  as  does  the  U.S.P.  for  alcohol  and,  in 
addition,  requires  that  dehydrated  alcohol  meet 
the  requirements  of  the  tests  for  alkaloids  and 
formaldehyde  under  Whisky. 

Absolute  (100  per  cent)  alcohol  has  a  specific 
gravity,  at  15.56°,  of  0.7936. 

The  tests  frequently  employed  to  prove  the 
absence  of  water  by  dropping  into  dehydrated 
alcohol  anhydrous  barium  oxide  or  anhydrous 
copper  sulfate  are  not  reliable,  as  Squibb  demon- 
strated that  when  one-half  of  one  per  cent  of 
water  is  added  to  absolute  alcohol  no  change  in 
either  the  barium  oxide  or  the  anhydrous  copper 
sulfate  took  place.  Gorgeu's  test  of  forming  a  clear 
solution  when  mixed  with  an  equal  bulk  of  pure 
benzene  is  more  delicate.  The  test  of  Henle  (Ber., 
1920,  53,  719)  is  capable  of  detecting  0.05  per 
cent  of  water  in  ethyl  alcohol;  in  this  test  a  solu- 
tion of  aluminum  ethoxide  in  benzene  forms  a 
voluminous  precipitate  when  added  to  ethyl  al- 
cohol containing  water. 

Uses. — Dehydrated  alcohol  is  sometimes  in- 
jected into  the  immediate  neighborhood  of  nerve 
ganglia,  or  even  into  the  spinal  cord,  for  the 
relief  of  pain  (see  also  under  Alcohol).  It  is  used 
as  a  reagent  in  certain  tests,  as  a  solvent  in  sys- 
tems where  water  must  be  excluded,  and  in  certain 
syntheses. 

Storage. — Preserve  "in  tight  containers,  re- 
mote from  fire."  N.F. 

DILUTED  ALCOHOL.    U.S.P. 

Diluted  Ethanol,  [Alcohol  Dilutum] 

"Diluted  Alcohol  is  a  mixture  of  alcohol  and 
water  containing  not  less  than  41  per  cent  and 
not  more  than  42  per  cent  by  weight,  correspond- 
ing to  not  less  than  48.4  per  cent  and  not  more 
than  49.5  per  cent  by  volume,  at  15.56°,  of 
C2H5OH."   U.S.P. 

The  B.P.  does  not  use  the  title  Diluted  Alcohol, 
but  gives  a  series  of  eight  formulas  for  prepara- 
tion of  Dilute  Alcohols  ranging  from  20  per  cent 
to  90  per  cent,  by  volume.  These  are  prescribed 
by  specifying  the  concentration  desired  as,  for 
example,  "Alcohol  (70  per  cent)." 


42  Alcohol,   Diluted 


Part   I 


The  I. P.  Dilute  Et Hanoi  contains  not  less  than 
69.1  per  cent  v/v  and  not  more  than  71  per  cent 
v/v,  corresponding  to  not  less  than  61.5  per  cent 
w/w  and  not  more  than  63.5  per  cent  w/w,  of 
CMoOH. 

Sp.  Alcohol  Diluido. 

The  U.S. P.  indicates  that  diluted  alcohol  may 
be  prepared  by  mixing  equal  volumes  of  alcohol 
and  purihed  water,  both  measured  at  the  same 
temperature.  At  25°  the  contraction  in  volume, 
after  cooling  the  mixture  to  the  same  tempera- 
ture, is  about  3  per  cent. 

Description  and  Tests. — "Diluted  Alcohol 
is  a  transparent,  colorless,  mobile  liquid,  having  a 
characteristic  odor  and  a  burning  taste.  The  spe- 
cific gravity  of  Diluted  Alcohol  is  not  less  than 
0.935  and  not  more  than  0.937  at  15. 56°,  indicat- 
ing not  less  than  41  per  cent  and  not  more  than 
42  per  cent  by  weight,  or  not  less  than  48.4  per 
cent  and  not  more  than  49.5  per  cent  by  volume, 
of  C2H5OH.  In  other  respects  Diluted  Alcohol 
complies  with  the  tests  under  Alcohol,  allowance 
being  made  for  the  difference  in  alcohol  concen- 
tration." U.S.P. 

Uses. — Diluted  alcohol  is  employed  chiefly  as 
a  menstruum  and  solvent  in  various  pharmaceu- 
tical manufacturing  processes.  When  the  thera- 
peutic effects  of  alcohol  are  desired  it  is  cus- 
tomary to  employ  either  whisky  or  brandy.  For 
description  of  the  physiologic  and  therapeutic 
properties,  see  under  Alcohol. 

Storage. — Preserve  "in  tight  containers,  re- 
mote from  fire."  U.S.P. 

ALCOHOL  RUBBING  COMPOUND. 

N.F. 

Rubbing  Alcohol,  [Alcohol  Fricamentum  Compositum] 

"Alcohol  Rubbing  Compound  and  all  prepara- 
tions coming  under  the  classification  of  Rubbing 
Alcohols  must  be  manufactured  in  accordance 
with  the  requirements  of  the  Internal  Revenue 
Service,  U.  S.  Treasury  Department,  using  spe- 
cially denatured  alcohol  Formula  23-G  (3.5  parts 
by  volume  of  methyl  propyl  ketone,  0.5  part  by 
volume  of  methyl  isobutyl  ketone,  and  100  parts 
by  volume  of  ethyl  alcohol),  or  Formula  23-H 
(8  parts  by  volume  of  acetone,  1.5  parts  by  vol- 
ume of  methyl  isobutyl  ketone,  and  100  parts  by 
volume  of  ethyl  alcohol).  It  contains  not  less  than 
68.5  per  cent  and  not  more  than  71.5  per  cent  by 
volume  of  absolute  ethyl  alcohol.  Alcohol  Rubbing 
Compound  contains  in  each  100  ml.  not  less  than 
355  mg.  of  sucrose  octaacetate.  Small  quantities  of 
perfume  oils  may  be  added  if  desired.  The  prep- 
aration may  also  be  colored  with  one  or  more 
coal-tar  colors,  certified  by  the  Food  and  Drug 
Administration  for  use  in  drugs.  A  suitable  stabi- 
lizer may  also  be  added.  Alcohol  Rubbing  Com- 
pound complies  with  the  requirements  of  the  In- 
ternal Revenue  Service  of  the  United  States 
Treasury  Department.  Note:  Alcohol  Rubbing 
Compound  must  be  packaged,  labeled  and  sold  in 
accordance  with  the  regulations  issued  by  the 
Internal  Revenue  Service,  U.  S.  Treasury  De- 
partment." N.F. 

Description. — "Alcohol  Rubbing  Compound 


is  a  transparent,  colorless  or  colored  as  desired, 
mobile,  and  volatile  liquid.  It  has  an  extremely 
bitter  taste,  and  in  the  absence  of  added  odorous 
constituents,  a  characteristic  odor.  It  is  flammable. 
The  specific  gravity  of  Alcohol  Rubbing  Com- 
pound, manufactured  with  specially  denatured 
alcohol  Formula  23-G,  is  not  less  than  0.8797  and 
not  more  than  0.8874,  and  the  specific  gravity  of 
Alcohol  Rubbing  Compound,  manufactured  with 
specially  denatured  alcohol  Formula  23-H  is  not 
less  than  0.8691  and  not  more  than  0.8771  at 
15.56°  (the  U.  S.  Government  standard  tempera- 
ture for  alcohol j."  N.F. 

Standards  and  Tests. — Non-volatile  residue. 
— The  weight  of  residue  obtained  by  evaporating 
25  ml.  of  alcohol  rubbing  compound  and  drying 
the  residue  at  105°  for  1  hour  is  not  less  than 
89  mg.  Methanol. — 0.5  ml.  of  a  dilution  of  0.5  ml. 
of  alcohol  rubbing  compound  to  1  ml.  with  water 
meets  the  requirements  of  the  test  for  methanol 
under  Whisky.  Assay  for  sucrose  octaacetate. — 
The  residue  from  the  test  for  non-volatile  residue 
is  neutralized  with  0.1  N  sodium  hydroxide,  using 
phenolphthalein  T.S.,  and  then  saponified  by  heat- 
ing with  a  measured  excess  of  0.1  N  sodium  hy- 
droxide. The  excess  alkali  is  titrated  with  0.1  N 
sulfuric  acid.  Each  ml.  of  0.1  N  sodium  hydroxide 
represents  8.482  mg.  of  sucrose  octaacetate  (the 
equivalent  is  based  on  the  formation  of  8  mole- 
cules of  acetic  acid  by  hydrolysis).  N.F. 

For  a  discussion  of  the  use  of  alcohol  exter- 
nally as  a  "rubbing  compound"  see  under  Al- 
cohol. The  N.F.  rubbing  alcohol  has  been  ren- 
dered unfit  for  beverage  use  and  is.  accordingly, 
available  at  a  much  lower  cost  to  the  consumer 
because  it  is  not  subject  to  the  regular  alcohol 
tax.  Under  no  circumstances  should  Alcohol  Rub- 
bing Compound  be  employed  in  place  of  alcohol. 

Storage. — Preserve  "in  tight  containers,  re- 
mote from  fire."  N.F. 

ALLYLBARBITURIC  ACID.  N.F. 

Allylisobutylbarbituric  Acid 


CH2CH=CH2 


CHCH(CH  ) 
2  32 


Sandoptal  (Sando:). 


Allylbarbituric  acid,  more  informatively  desig- 
nated 5-allyl-5-isobutylbarbituric  acid,  may  be 
prepared  by  the  method  described  by  Yolwiler 
(J.A.C.S.,  1925,  47,  2236)  in  which  the  diethyl 
ester  of  mono-isobutylmalonic  acid  is  condensed 
with  urea,  producing  mono-isobutylbarbituric  acid, 
into  which  is  introduced  the  allyl  substituent  by 
interaction  with  allyl  bromide  in  sodium  hydroxide 
solution.  Acidification  of  the  reaction  mixture  pre- 
cipitates the  5-allyl-5-isobutylbarbituric  acid. 

Description. — "Allylbarbituric  Acid  occurs  as 
a  white,  crystalline,  odorless  powder,  with  a 
slightly  bitter  taste.  It  is  stable  in  air.  A  saturated 
solution  is  acid  to  litmus  paper.  Allylbarbituric 
Acid  is  freely  soluble  in  alcohol,  in  ether,  and  in 
chloroform ;  it  is  slightly  soluble  in  cold  water  and 
soluble  in  boiling  water.  It  is  soluble  in  solutions 


Part  I 


Almond  Oil,  Bitter         43 


of  fixed  alkalies  and  carbonates.  Allylbarbituric 
Acid  melts  between  138°  and  139°."  N.F. 

Standards  and  Tests. — Identification. — (1) 
A  filtered  solution  of  300  mg.  of  allylbarbituric 
acid  in  a  mixture  of  1  ml.  of  1  N  sodium  hydrox- 
ide and  5  ml.  of  water  is  divided  into  two  por- 
tions: one  portion  yields  with  1  ml.  of  mercury 
bichloride  T.S.  a  white  precipitate,  soluble  in  10 
ml.  of  ammonia  T.S.;  the  other  portion  yields 
with  5  ml.  of  silver  nitrate  T.S.  a  white  precipi- 
tate, soluble  in  5  ml.  of  diluted  ammonia  solu- 
tion. (2)  On  boiling  500  mg.  of  the  acid  with 
5  ml.  of  1  in  4  sodium  hydroxide  solution  am- 
monia is  evolved.  (3)  A  saturated  solution  of 
allylbarbituric  acid  in  water  is  prepared:  on  add- 
ing 1  ml.  of  acetic  acid  and  0.5  ml.  of  bromine 
T.S.  to  5  ml.  of  the  solution  the  bromine  color  is 
discharged  immediately;  on  adding  0.1  ml.  of 
potassium  permanganate  T.S.  to  another  5  ml. 
portion  of  the  solution  a  yellow  color  appears  im- 
mediately, turning  to  brown.  Loss  on  drying. — 
Not  over  1  per  cent,  when  dried  at  105°  for  2 
hours.  Residue  on  ignition. — Not  over  0.1  per 
cent.  Heavy  metals. — About  100  mg.  of  allyl- 
barbituric acid  is  boiled  with  10  ml.  of  water  for 
2  minutes,  cooled,  and  filtered:  on  saturating  the 
filtrate  with  hydrogen  sulfide  no  coloration  or  pre- 
cipitation results.  Readily  carbonizable  substances. 
— A  solution  of  500  mg.  of  the  allylbarbituric 
acid  in  5  ml.  of  sulfuric  acid  has  no  more  color 
than  matching  fluid  A.  N.F. 

Uses. — Allylbarbituric  acid  (see  article  on 
Barbiturates,  in  Part  II,  for  general  discussion) 
has  been  classified  as  being  a  barbiturate  of  inter- 
mediate duration  of  action,  according  to  the  sys- 
tem of  Fitch  and  Tatum  (/.  Pharmacol.,  1932, 
44,  325).  Its  duration  of  action  is  of  an  order 
comparable  with  that  of  aprobarbital  and  of  amo- 
barbital  (Tatum,  Physiol.  Rev.,  1939,  19,  472). 
In  general,  it  is  employed  as  an  hypnotic  agent 
or  for  mild  sustained  sedation.  In  this  respect  its 
clinical  indications  are  much  the  same  as  for  bar- 
bital or  amobarbital. 

Allylbarbituric  acid  is  metabolized  primarily 
in  the  liver,  according  to  Masson  and  Beland 
(Anesth.,  1945,  6,  483).  Only  trace  amounts  are 
excreted  as  such  by  normal  patients  (Koppanyi 
et  al.,  J.  Pharmacol.,  1934,  52,  87).  Staub  re- 
ported that  some  20  per  cent  of  the  daily  dose 
administered  to  schizophrenic  patients  was  ex- 
creted as  such  (Schweiz.  Arch.  Neurol.  Psychiat., 
1950,  65,  330).  Allylbarbituric  acid  apparently 
possesses  no  toxicologic  characteristics  that  are 
not  shared  on  a  pharmacodynamic  basis  with  other 
barbiturates.  Nielsen  et  al.  (J.  Pharmacol.,  1925, 
26,  371)  found  that  the  minimum  lethal  dose  of 
allylbarbituric  acid,  when  the  sodium  salt  was  in- 
jected subcutaneously  into  white  rats,  was  175 
mg.  per  Kg.  of  body  weight,  with  the  ratio  of 
minimum  effective  dose  to  minimum  lethal  dose 
being  next  to  the  most  favorable  for  the  series  of 
15  barbiturates  which  they  investigated. 

Dose. — For  sedation  the  dose  range  is  100  to 
200  mg.  (approximately  l/2  to  3  grains);  the 
hypnotic  dose  varies  from  200  to  800  mg.,  the 
higher  doses  being  used  in  obstinate  cases  of 
insomnia. 


Storage. — Preserve  "in  well-closed  contain- 
ers." N.F. 

ALLYLBARBITURIC  ACID 
TABLETS.  N.F. 

"Allylbarbituric  Acid  Tablets  contain  not  less 
than  94  per  cent  and  not  more  than  106  per  cent 
of  the  labeled  amount  of  C11H16N2O3."  N.F. 

The  assay  is  identical  with  that  described  under 
Barbital  Tablets. 

Usual  Size. — 200  mg.  (approximately  3 
grains). 


BITTER  ALMOND   OIL. 

[Oleum  Amygdalae  Amarae] 


N.F. 


"Bitter  Almond  Oil  is  the  volatile  oil  obtained 
from  the  dried  ripe  kernel  (deprived  of  fixed  oil) 
of  Primus  Amygdalus  Batsch  var.  amara  (De 
Candolle)  Focke  (Fam.  Rosacea),  or  from  other 
kernels  containing  amygdalin,  by  maceration  with 
water  and  subsequent  distillation  with  steam.  It 
contains  not  less  than  80  per  cent  of  CgHs.CHO, 
and  not  less  than  2  per  cent  and  not  more  than  4 
per  cent  of  HCN.  Bitter  Almond  Oil  in  which 
crystals  have  formed  must  not  be  dispensed. 

''Caution. — Bitter  Almond  Oil  is  intended  for 
medicinal  use  and  neither  it  nor  its  solution  should 
be  used  or  sold  for  flavoring  foods."  N.F. 

This  should  not  be  confused  with  the  B.P. 
Volatile  Bitter  Almond  Oil,  which  contains  no 
hydrocyanic  acid. 

Oil  of  Bitter  Almond.  Oleum  Amygdalarum  Amararum 
^Ethereum.  Fr.  Essence  d'amande  amere.  Ger.  Atherisches 
Bittermandelol.  Sp.  Esencia  de  almendre  amarga. 

The  almond  tree — Prunus  Amygdalus  Batsch 
(Amygdalus  communis  Linne) — resembles  some- 
what the  cherry.  The  leaves  are  elliptical, 
petiolate,  minutely  serrated,  and  are  of  a  bright 
green  color.  The  flowers  are  large,  varying  from 
pink  to  white,  with  very  short  peduncles,  and 
petals  longer  than  the  calyx,  and  usually  stand  in 
pairs  upon  the  branches.  The  fruit  is  a  drupe  with 
the  outer  covering  thin,  tough,  dry,  downy,  and 
marked  with  a  longitudinal  furrow,  where  it  opens 
when  fully  ripe.  Within  this  covering  is  a  rough 
shell,  containing  the  kernel  or  almond. 

There  are  several  varieties  of  this  species  of 
Prunus,  differing  chiefly  in  the  size  and  shape  of 
the  fruit,  the  thickness  of  the  shell,  and  the  taste 
of  the  kernel.  The  two  most  important  are  the 
var.  dulcis  and  the  var.  amara,  the  former  bearing 
sweet,  the  latter  bitter,  almonds.  Both  of  these 
varieties  have  been  known  since  ancient  times. 
The  almond  tree  is  a  native  of  subtropical  Asia 
and  Asia  Minor.  It  is  now  cultivated  also  in 
southern  Europe,  northern  Africa,  southern  Eng- 
land, and  California.  Bitter  almonds  are  chiefly 
imported  from  France,  Morocco  and  Sicily.  Bitter 
almond  oil  is  usually  imported  from  France, 
United  Kingdom  and  Netherlands.  In  1952  these 
countries  shipped  3777  pounds  to  the  United 
States. 

Bitter  Almonds. — These  seeds  are  smaller  than 
the  sweet  almonds,  which  they  resemble  in  gen- 
eral appearance,  but  are  distinguished  by  being 
shorter  and  proportionally  broader,  by  their  bitter 
taste,  and  by  the  characteristic  odor  resembling 


44  Almond   Oil,   Bitter 


Part  I 


that  of  hydrocyanic  acid  when  they  are  bruised 
in  a  mortar  and  triturated  with  water. 

They  have  the  bitter  taste  of  the  peach  kernel, 
and,  though  when  dry.  are  inodorous  or  nearly  so, 
have,  when  triturated  with  water,  the  fragrance 
of  peach  blossom.  They  contain  essentially  the 
same  constituents  as  sweet  almonds,  and  like  them 
form  a  milky  emulsion  with  water.  Their  char- 
acteristic flavor  is  due  to  the  formation  of  benz- 
aldehyde  and  hydrocyanic  acid.  These  principles 
do  not  preexist  in  the  almond,  but  result  from 
the  decomposition  of  the  glycoside  amygdalin. 
Amygdalin  is  mandelonitrile-p-gentiobioside,  a 
glycoside  of  mandelonitrile,  CoHsCHOHCN,  with 
gentiobiose,  a  disaccharide  formed  by  the  conden- 
sation of  two  glucose  molecules.  It  is  white,  crys- 
tallizable,  inodorous,  of  a  sweetish  bitter  taste, 
freely  soluble  in  water  and  hot  alcohol,  very 
slightly  soluble  in  cold  alcohol,  and  insoluble  in 
ether.  It  is  hydrolyzed  in  the  presence  of  diluted 
acids  or  the  enzyme  emulsin,  which  accompanies 
it  in  bitter  almond.  Destruction  of  emulsin,  as  by 
heating,  prevents  the  hydrolysis  of  amygdalin 
and  consequently  of  the  development  of  the  char- 
acteristic flavor  of  bitter  almond. 

Mandelonitrile  glucosides  occur  in  three  iso- 
meric forms:  sambunigrin  found  in  elder  flowers, 
priilanrasin  found  in  cherry  laurel,  and  prunasin 
found  in  wild  cherry  bark.  All  of  these  are  op- 
tically active,  being  levorotatory,  but  vary  in 
the  degree  of  rotation.  According  to  Power  and 
Moore  {Trans.  Chem.  Soc,  1909,  p.  243)  they  are 
combinations  of  dextro-,  racemic  and  levo-man- 
delonitrile.  respectively  (see  also  Fischer  and 
Bergmann,  Ber.,  1917,  50,  1047). 

Description. — "Bitter  Almond  Oil  is  a  clear, 
colorless  or  yellow,  strongly  refractive  liquid,  hav- 
ing the  characteristic  odor  and  taste  of  benzalde- 
hyde.  Bitter  Almond  Oil  is  slightly  soluble  in 
water.  It  is  miscible  with  alcohol  and  with  ether. 
Bitter  Almond  Oil  is  soluble  in  2  volumes  of  70 
per  cent  alcohol,  forming  a  clear  solution.  The 
specific  gravity  of  Bitter  Almond  Oil  is  not  less 
than  1.05S  and  not  more  than  1.060  at  25V  N.F 

Standards  and  Tests. — Optical  rotation. — 
Bitter  almond  oil  is  optically  inactive  or  does  not 
have  a  rotation  of  more  than  +0.167°  when  de- 
termined in  a  100-mm.  tube  at  25°.  Refractive 
index. — Not  less  than  1.5410  nor  more  than 
1.5442  at  20°.  Heavy  metals. — The  oil  complies 
with  the  requirements  of  the  official  test  for 
Heavy  metals  in  volatile  oils.  Halogens. — No 
turbidity  is  produced  when  silver  nitrate  T.S.  is 
added  to  products  of  the  combustion  of  3  or  4 
drops  of  bitter  almond  oil  which  have  been  con- 
densed on  the  moistened  inside  of  an  inverted 
beaker  after  the  oil  is  ignited.  Nitrobenzene. — 
No  odor  of  phenyl  isocyanide  is  apparent  on 
heating  bitter  almond  oil,  in  which  any  nitroben- 
zene that  may  be  present  has  been  reduced  with 
nascent  hydrogen  to  aniline,  with  chloroform  and 
sodium  hydroxide  T.  S.  N.F. 

Nitrobenzene  was  at  one  time  a  frequent  adul- 
terant of  bitter  almond  oil.  It  may  be  detected 
by  the  test  given  above. 

Assay. — For  benzaldehyde. — A  sample  of 
about  1  Gm.  of  the  oil  is  reacted  with  a  hydro- 
alcoholic  solution  of  hydroxylamine  hydrochloride, 


with  which  the  benzaldehyde  forms  benzaldoxime 
and  liberates  a  molecule  of  hydrogen  chloride  for 
each  molecule  of  aldehyde  present.  The  acid  is 
titrated  with  1  A7  sodium  hydroxide.  After  cor- 
recting for  the  acidity  of  the  reagent  each  ml.  of 
1  N  sodium  hydroxide  is  equivalent  to  106.1  mg. 
of  C-HoO.  N.F.  For  hydrogen  cyanide. — To  some 
freshly  prepared  magnesium  hydroxide  suspension 
is  added  1  Gm.  of  the  oil,  whereby  the  benzalde- 
hyde cyanhydrin  releases  cyanide  ion  which  is 
titrated  with  0.1  A7  silver  nitrate,  using  potassium 
chromate  T.S.  as  indicator,  until  a  permanent  red 
coloration  is  produced.  Any  impurities  in  the 
magnesium  hydroxide  suspension  which  may  react 
with  silver  nitrate  are  corrected  for  by  titrating 
the  suspension  prior  to  addition  of  the  oil.  Each 
ml.  of  0.1  N  silver  nitrate  represents  2.703  mg. 
of  HCN.  N.F. 

Uses. — As  benzaldehyde  has  no  recognized 
medicinal  action,  bitter  almond  oil  acts  physio- 
logically like  hydrocyanic  acid.  Death  is  said  to 
have  occurred  in  a  man  ten  minutes  after  taking 
two  fluidrachms  of  the  oil.  Bitter  almond  oil  has 
been  employed  externally,  dissolved  in  water  in 
the  proportion  of  one  minim  (0.06  ml.)  to  a  fluid- 
ounce  (30  ml.),  in  prurigo  senilis  and  other  cases 
of  troublesome  itching.  To  facilitate  solution  in 
water,  the  oil  may  be  previously  dissolved  in  alco- 
hol. Bitter  almond  oil  has  been  used  to  conceal 
the  taste  of  cod  liver  oil  and  of  castor  oil.  It  also 
finds  some  use  as  a  perfuming  agent  in  cosmetic 
preparations. 

Amygdalin  itself  is  practically  non-toxic,  but 
when  swallowed  may  be  decomposed,  by  enzymes 
present  in  ingested  foods  in  the  alimentary  canal, 
leading  to  the  formation  of  hydrocyanic  acid. 

Storage. — Preserve  "in  well-filled,  tight  con- 
tainers, and  avoid  exposure  to  excessive  heat." 
N.F. 

PURIFIED  VOLATILE  OIL  OF 
BITTER  ALMOND.     B.P. 

Oleum  Amygdalae  Volatile  Purificatum 

This  is  a  very  different  preparation  from  the 
N.F.  Bitter  Almond  Oil.  The  B.P.  oil  is  prepared 
from  the  cake  of  seeds  of  bitter  almonds,  peach 
kernels  or  apricot  kernels,  from  which  the  fixed 
oil  has  been  expressed,  by  distilling  with  water 
and  subsequently  removing  the  hydrocyanic  acid. 
It  should  contain  not  less  than  95.0  per  cent 
w  w  of  benzaldehyde. 

The  B.P.  does  not  mention  any  method  for  re- 
moving the  hydrocyanic  acid  but  this  may  be  ac- 
complished by  treating  the  oil  with  ferrous  sulfate 
and  calcium  hydroxide,  followed  by  redistillation. 

Description  and  Standards. — This  is  a 
colorless  or  pale  yellow  liquid  with  the  character- 
istic odor  and  taste  of  bitter  almonds.  Its  weight 
per  ml.,  at  20°,  is  1.042  to  1.046;  it  has  a  re- 
fractive index  at  20°  of  1.542  to  1.546.  It  is 
soluble  in  two  parts  of  70  per  cent  alcohol.  The 
absence  of  hydrocyanic  acid  is  shown  by  shaking 
the  oil  with  sodium  hydroxide  solution,  adding 
ferrous  sulphate  solution,  warming  and  acidulating 
with  dilute  hydrochloric  acid;  no  blue  color 
should  be  produced.  A  test,  in  which  an  alcohol 
solution  of  the  oil  is  titrated  with  0.1  N  alcoholic 


Part  I 


Almond   Oil,   Expressed  45 


potassium  hydroxide,  limits  the  amount  of 
benzoic  acid  which  may  be  present. 

Assay. — This  is  essentially  similar  to  the 
method  employed  for  the  assay  of  benzaldehyde 
in  bitter  almond  oil  or  in  the  official  product 
benzaldehyde. 

This  oil  is  intended  as  a  flavoring  agent  for  the 
same  purposes  as  benzaldehyde.  The  B.P.  uses  it 
as  a  flavor  for  emulsion  of  cod  liver  oil. 

EXPRESSED  ALMOND  OIL. 

U.S.P.  (B.P.) 

Almond  Oil,  Sweet  Almond  Oil,   [Oleum  Amygdalae 
Expressum] 

"Expressed  Almond  Oil  is  the  fixed  oil  obtained 
from  the  kernels  of  varieties  of  Prunus  Amygdalus 
Batsch  (Fam.  Rosacea)."  U.S.P.  The  B.P.  rec- 
ognizes as  the  sources  of  this  oil  the  seeds  of 
Primus  amygdalus  Batsch.  var.  dulcis  (DC.) 
Koehne,  or  of  Prunus  amygdalus  Batsch.  var. 
amara  (DC.)  Focke. 

B.P.  Almond  Oil;  Oleum  Amygdalae.  Oil  of  Sweet  Al- 
mond. Oleum  Amygdalarum.  Ft.  Huile  d'arr.ande.  Ger. 
Mandeldl.  It.  Olio  di  mandorle  dolci.  Sp.  Aceite  de 
almendras;  Aceite  de  Almendra  por  Expresion. 

For  description  of  Prunus  Amygdalus  Batsch, 
also  known  as  Primus  communis  Arcang.,  see 
under  Bitter  Almond  Oil. 

In  normal  times  we  are  supplied  with  sweet 
almonds  chiefly  from  Spain,  Italy,  France,  and 
southern  California.  They  are  separated  into  the 
soft-shelled  and  hard-shelled  varieties,  the  former 
of  which  come  from  Marseilles  and  Bordeaux,  the 
latter  from  Malaga.  From  the  latter  port  they 
are  sometimes  exported  without  the  shell.  In 
British  commerce,  the  two  chief  varieties  are  the 
Jordan  and  Valencia  almonds,  the  former  im- 
ported from  Malaga,  the  latter  from  Valencia; 
the  former  are  longer,  narrower,  more  pointed, 
and  more  highly  esteemed  than  the  latter.  Each 
kernel  consists  of  two  white  cotyledons,  enclosed 
in  a  thin,  yellowish-brown,  bitter  skin,  which  is 
easily  separable  after  immersion  in  boiling  water. 
Deprived  of  this  covering  they  are  called  blanched 
almonds.  On  exposure  to  the  air  they  are  apt  to 
become  rancid;  but,  if  thoroughly  dried  and  kept 
in  well-closed  glass  vessels,  they  may  be  pre- 
served unaltered  for  many  years.  They  are,  when 
blanched,  without  odor,  and  have  a  sweet,  pleas- 
ant taste,  which  has  rendered  them  a  favorite 
article  of  diet  in  all  countries  where  they  are 
readily  attainable. 

Sweet  almonds  are  no  longer  official.  The  B.P. 
1914  described  them,  under  the  name  Amygdala 
Dulcis,  as  follows : 

"About  two  and  a  half  centimeters  or  some- 
what more  in  length,  nearly  oblong  in  outline, 
more  or  less  compressed,  pointed  at  one  extrem- 
ity and  rounded  at  the  other.  Testa  cinnamon- 
brown,  thin  and  scaly.  Seed  exalbuminous,  con- 
taining two  large  planoconvex  oily  cotyledons. 
Taste  bland;  when  triturated  with  water  forms  a 
white  emulsion  with  no  marked  odor."  B.P.  1914. 

The  U.S.P.  IX  gave  the  following  description  of 
microscopic  appearance.  "The  powder  is  creamy- 
white,  exhibiting  numerous  very  small  oil  globules, 
0.001  mm.  or  less  in  diameter,  and  larger  oil 
globules  and  crystalloids,   the   latter  sometimes 


with  adhering  globoids;  fragments  of  parenchyma 
of  endosperm,  containing  oil  globules  and  aleurone 
grains;  also  occasional  fragments  of  seed-coat 
with  characteristic,  more  or  less  scattered,  large, 
elliptical,  thin-walled,  strongly  lignified  epidermal 
cells  and  narrow,  closely  spiral  tracheae.  Starch 
grains  are  absent."  U.S.P.  IX. 

Sweet  almonds  contain  up  to  about  54  per  cent 
of  fixed  oil,  24  per  cent  of  protein,  6  per  cent  of 
uncrystallizable  sugar,  3  per  cent  of  gum,  9  per 
cent  of  fibrous  matter,  3.5  per  cent  of  water,  and 
0.5  per  cent  of  acetic  acid.  They  yield  the  enzyme 
emulsion  but  do  not  contain  amygdalin.  "Almond 
cake,"  a  by-product  in  the  manufacture  of  almond 
oil,  is  largely  used  in  the  preparation  of  a  class 
of  detergent  powders  known  as  "almond  meal." 
It  is  also  used  as  a  diabetic  food  and  sometimes 
as  an  adulterant  of  ground  spices  and  powdered 
drugs.  Almond  cake  may  be  poisonous  if  it  is 
made  with  bitter  almond  as  it  would  contain 
emulsin  and  amygdalin  and  yield  hydrocyanic 
acid. 

Expressed  almond  oil  may  be  obtained  equally 
pure  from  sweet  and  from  bitter  almonds.  In  its 
preparation,  the  almonds,  deprived  of  a  reddish- 
brown  powder  adhering  to  their  surface  by  being 
rubbed  together  in  a  piece  of  coarse  linen,  are 
ground  in  a  mill  or  bruised  in  a  stone  mortar,  and 
then  pressed  in  canvas  sacks  between  slightly 
warm  plates  of  iron.  The  oil,  which  is  at  first 
turbid,  is  clarified  by  filtration.  Sometimes  the 
almonds  are  steeped  in  hot  water,  deprived  of 
their  cuticle,  and  dried  by  heating,  previous  to 
expression.  The  oil  thus  obtained  is  free  from 
color,  but  is  in  no  other  respect  better;  it  is  more 
likely  to  become  rancid  on  keeping.  Bitter  almonds 
treated  in  this  way  impart  an  odor  of  hydrocyanic 
acid  to  the  oil.  The  yield  of  oil  from  sweet 
almond  is  from  40  to  55  per  cent,  being  slightly 
less  from  the  bitter.  Though  sometimes  expressed 
in  this  country  from  imported  almonds,  the  oil  is 
generally  brought  from  Europe.  During  World 
War  II,  when  the  oil  was  not  available,  the 
U.S.P.  permitted  the  use  of  persic  oil  in  ointments 
in  which  expressed  almond  oil  is  an  ingredient. 

Description. — "Expressed  Almond  Oil  is  a 
clear,  pale  straw-colored  or  colorless,  oily  liquid. 
It  is  almost  odorless,  and  has  a  bland  taste.  It  re- 
mains clear  at  —10°,  and  does  not  congeal  until 
cooled  to  nearly  — 20°.  Expressed  Almond  Oil  is 
slightly  soluble  in  alcohol,  but  is  miscible  with 
ether,  with  chloroform,  with  benzene,  and  with 
petroleum  benzin.  The  specific  gravity  of  Ex- 
pressed Almond  Oil  is  not  less  than  0.910  and  not 
more  than  0.915."  U.S.P. 

Standards  and  Tests. — Foreign  kernel  oils. — 
Not  more  than  a  slight  color  develops  on  shaking 
vigorously  for  5  minutes  a  mixture  of  2  ml.  of  ex- 
pressed almond  oil,  1  ml.  of  fuming  nitric  acid  and 
1  ml.  of  water.  Cottonseed  or  sesame  oil. — The 
oil  meets  the  requirements  of  the  tests  for  cotton- 
seed oil  and  for  sesame  oil  under  Olive  Oil.  Min- 
eral oil  and  foreign  fatty  oils. — A  clear  solution 
results  on  adding  water  to  the  residue  remaining 
after  the  evaporation  of  the  alcohol  from  a  mix- 
ture of  expressed  almond  oil,  sodium  hydroxide 
solution,  and  alcohol  which  has  been  heated  to 
saponify  the  oil  {mineral  oil).  On  adding  an  ex- 


46  Almond   Oil,   Expressed 


Part  I 


cess  of  hydrochloric  acid  to  the  aqueous  solution 
the  fatty  acids  which  separate,  after  washing  with 
warm  water  and  clarifying  by  heating  on  a  water 
bath,  remain  clear  for  at  least  30  minutes  when 
cooled  to  15°  and  kept  at  this  temperature,  with- 
out stirring.  Foreign  oils. — A  clear  solution  re- 
sults when  a  portion  of  the  fatty  acids  separated 
in  the  preceding  test  is  mixed  with  an  equal  vol- 
ume of  alcohol  and  cooled  to  15° ;  no  turbidity  de- 
velops on  adding  another  volume  of  alcohol  (olive, 
peanut,  or  other  fixed  oils).  Free  fatty  acids. — 
Not  more  than  5  ml.  of  0.1  N  sodium  hydroxide  is 
required  for  neutralization  of  10  Gm.  of  oil. 
Iodine  value. — Not  less  than  95  and  not  more 
than  105.  Saponification  value. — Not  less  than 
190  and  not  more  than  200.  U.S.P. 

The  B.P.  gives  the  refractive  index,  at  40°,  as 
1.4624  to  1.4650,  and  the  acid  value  as  not  more 
than  4.0. 

Expressed  almond  oil  consists  chiefly  of  olein 
with  traces  of  linolein;  there  is  no  stearin  present. 
It  belongs  among  the  "non-drying"  oils  or  "vege- 
table oleins." 

Expressed  almond  oil  has  been  adulterated  with 
oils  from  peach  or  apricot  kernels,  olive  oil,  lard 
oil,  cottonseed  oil,  and  peanut  oil;  these  may  be 
detected  by  the  official  tests.  Many  of  these 
adulterants  may  also  be  detected  by  determining 
the  absorption  spectrum  of  the  sample.  Almond 
oil  differs  from  most  vegetable  oils  in  neither 
giving  a  banded  spectrum  nor  producing  strong 
absorption  in  the  red  or  violet. 

Uses. — Expressed  almond  oil  possesses  the 
emollient  properties  of  the  other  fixed  oils,  over 
most  of  which  it  has  the  advantage  of  comparative 
tastelessness,  freedom  from  odor,  and  lack  of 
tendency  to  become  gummy.  It  is  widely  used 
as  an  emollient  for  chapped  hands  and  other  in- 
flamed conditions  of  the  skin.  The  oil  is  some- 
times employed  in  the  preparation  of  cold  creams, 
as  in  the  official  rose  water  ointment,  and  in 
similar  cosmetic  preparations.  Occasionally  it  is 
used  for  its  laxative  effect. 

Dose,  4  to  30  ml.  (approximately  one 
fluidrachm  to  one  fluidounce). 

Storage. — Preserve  "in  tight  containers." 
U.S.P. 

Off.  Prep.— Rose  Water  Ointment,  US.P. 

ALOE.     U.S.P.  (B.P.) 

Aloes,  [Aloe] 

"Aloe  is  the  dried  juice  of  the  leaves  of  Aloe 
Perryi  Baker,  known  in  commerce  as  Socotrine 
Aloe,  or  of  Aloe  barbadensis  Miller  (Aloe  vera 
Linne'),  known  in  commerce  as  Curasao  Aloe,  or 
of  Aloe  ferox  Miller  and  hybrids  of  this  species 
with  Aloe  africana  Miller  and  Aloe  spicata  Baker, 
known  in  commerce  as  Cape  Aloe  (Fam.  Lili- 
acetz).  Aloe  yields  not  less  than  50  per  cent  of 
water-soluble  extractive."  U.S.P. 

The  B.P.  recognizes  Aloes  as  the  residue  ob- 
tained by  evaporating  to  dryness  the  liquid  which 
drains  from  leaves  cut  from  various  species  of 
Aloe.  Not  less  than  75.0  per  cent  of  water- 
soluble  extractive  is  required. 

B.P.  Aloes.  Fr.  Aloes.  Cer.  Aloe.  It.  Aloe.  Sp.  Acibar; 
Aloe. 


The  genus  Aloe  comprises  about  170  species 
mostly  native  to  eastern  and  southern  Africa,  but 
some  have  spread  to  the  Mediterranean  basin 
and  have  been  introduced  into  the  West  Indies, 
East  Indies,  Europe,  and  the  Americas.  The  leaves 
of  the  Aloe  plants  are  fleshy  and  succulent.  In 
cross  section  they  exhibit  a  strongly  cuticularized 
epidermis  surrounding  a  mesophyll  of  two  zones, 
viz.:  an  outer  cortical  zone  composed  of  paren- 
chyma containing  numerous  chloroplastids,  as- 
similation starch  and  occasional  bundles  of 
raphides  of  calcium  oxalate,  and  an  inner,  clear 
central  zone  consisting  of  large,  thin-walled 
parenchyma  with  an  abundance  of  mucilage  and 
scattered  cells  containing  raphides  of  calcium 
oxalate.  On  the  border  of  the  outer  cortical  and 
clear  central  zones  is  to  be  noted  an  ellipse  of 
vascular  bundles  each  of  which  is  surrounded  by 
a  pericycle  and  endodermis.  The  bitter  juice  is 
contained  within  the  pericyclic  cells  and  some- 
times in  the  parenchyma  cells  adjacent. 

Most  plants  belonging  to  the  genus  are  capable 
of  yielding  a  bitter  juice  which  is  laxative  and 
there  is  little  doubt  that  in  many  cases  a  com- 
mercial aloe  exported  from  one  country  is  the 
product  of  the  leaves  of  several  species. 

1.  Aloe  Perryi  Baker. — The  true  Socotrine  aloe 
is  a  perennial  herb,  growing  abundantly  upon  the 
island  of  Socotra,  especially  in  the  limestone 
tracts,  from  the  sea  level  to  an  altitude  of  3,000 
feet  and  also  found  in  eastern  Africa  and  in 
Arabia.  It  has  a  trunk  one  foot  high  which  bears 
on  its  summit  a  dense  rosette  of  pale  green  or 
reddish,  succulent,  lanceolate  leaves  which  are 
somewhat  striate  but  not  mottled.  They  are 
channeled  above,  convex  below  and  show  brown- 
tipped,  marginal  spines.  From  the  center  of  the 
leaf  rosette  there  extends  a  long  raceme  of  tubu- 
lar, reddish  flowers  which  later  turn  yellow.  The 
fruit  is  a  membranous  capsule. 

2.  Aloe  barbadensis  Mill.  (A.  vera  "L.";  A. 
vulgaris  Lamarck). — This  species,  which  is  the 
source  of  Curasao  aloe,  has  a  very  short,  woody 
stem,  and  lanceolate  embracing  leaves,  which  are 
first  spreading,  then  ascending,  of  a  glaucous 
green  color,  when  young,  irregularly  mottled  with 
white  spots,  flat  on  the  upper  surface,  convex 
beneath,  and  armed  with  hard,  pale  spines,  dis- 
tant from  each  other,  and  perpendicular  to  the 
margin.  It  has  bright  yellow  flowers  arranged  in 
a  spicate  inflorescence.  A.  barbadensis  is  a  native 
of  southeastern  Europe,  northern  Africa,  and 
Madagascar.  It  is  cultivated  in  Italy,  Sicily, 
Malta,  and  especially  in  the  West  Indies,  where 
it  contributes  largely  in  the  Curacao  or  Barbados 
aloe. 

3.  Aloe  ferox  Miller,  one  of  the  three  South 
African,  tree-like  species  yielding  Cape  aloe,  is 
one  of  the  tallest  species  of  the  genus.  It  has  a 
forked  stem  ten  to  fifteen  feet  long,  four  to  six 
inches  in  diameter;  furnished  at  the  top  with  a 
dense  rosette  containing  thirty  to  fifty  leaves, 
which  are  lanceolate,  one  and  one-half  to  two 
feet  long,  very  rigid,  with  copious  prickles  on 
back  and  face,  the  purplish  margin  armed  with 
reddish  brown-tipped,  deltoid  or  cuspidate  prickles 
one-eighth  to  one-sixth  of  an  inch  long.  Its  in- 
florescence consists  of  a  panicle  of  tubular,  striped 


Part  I 


Aloe 


47 


whitish  flowers.  This  species  readily  hybridizes 
with  A.  africana  and  A.  spicata  and  hybrids  of 
these  yield  some  of  the  Cape  aloes  of  the  market. 

4.  Aloe  africana  Mill.,  an  arborescent  South 
African  species,  has  a  simple  tall  trunk  which 
bears  on  its  summit  a  few  triangular-oblong, 
glaucous,  green  leaves  with  large,  horny,  mar- 
ginal teeth.  Its  flowers  are  tubular  and  yellow 
and  are  borne  on  a  candelabra-like  panicle.  It  is 
a  native  of  the  Cape  Colony. 

5.  Aloe  spicata  Baker  {A.  Eru  var.  cornuta 
Berger)  is  a  tall,  branched  aloe  indigenous  to 
tropical  southern  Africa.  It  possesses  pale,  glossy, 
fleshy  leaves  with  white  blotches  and  a  panicle 
of  campanulate  yellow  flowers. 

For  further  details  on  species  of  Aloe,  see 
Baker  (Jour.  Linnean  Soc,  Botany,  Vol.  1880, 
pp.  148-241). 

Commercial  History  and  Varieties. — 

Socotrine  Aloe. — This  variety  appears  to  have 
been  the  original  aloe,  having  been  produced  in 
the  island  of  Socotra  at  least  as  early  as  the  time 
of  Alexander  the  Great,  333  B.C.,  who  is  said  to 
have  sent  a  commission  to  investigate  its  manu- 
facture. 

The  leaves,  which  are  cut  at  any  time  of  year, 
are  allowed  to  drain  into  a  goat's  or  sheep's  skin, 
and  the  gathered  juice  permitted  to  evaporate 
spontaneously.  In  the  course  of  about  one  month, 
when  it  has  become  thick  and  viscid,  it  is  known 
by  the  Arabic  name  of  Jayef  Gesheeshah ;  several 
weeks  subsequently  when  it  has  become  hard,  it  is 
called  Jayef  Kasahul.  Due  to  its  exposure  through- 
out the  long  process  of  desiccation,  all  the 
varieties  of  Socotrine  aloes  contain  much  foreign 
matter. 

Socotrine  aloe  is  brought  from  the  island  of 
Socotra,  the  east  coast  of  Africa,  and  from  the 
Arabian  coast  by  Arab  traders  to  Bombay  and 
exported  in  barrels,  kegs,  goats'  skins,  or  tins 
to  London,  whence  it  is  shipped  to  the  United 
States. 

The  best  Socotrine  aloe  occurs  in  pieces  vary- 
ing from  a  dark  ruby-red  to  a  yellowish  or  red- 
dish-brown, more  or  less  semi-transparent,  with 
a  glossy  surface  and  a  smooth  or  ragged  but  not 
conchoidal  fracture,  and  yielding  a  bright  golden- 
yellow  powder.  Its  odor  is  peculiar,  almost 
fragrant,  especially  developed  by  breathing  upon 
the  aloe,  and  its  bitter,  disagreeable  taste  has  a 
somewhat  aromatic  tang.  The  poorest  variety  of 
Socotrine  aloe,  Mocha  aloes  of  the  East,  is  soft, 
dark,  and  malodorous. 

Zanzibar  Aloe  is  a  hepatic  variety  of  Socotrine 
aloe  made  by  slow  evaporation  of  the  juice.  It 
occurs  in  liver-brown  masses,  with  a  dull,  waxy 
but  nearly  smooth  and  even  fracture,  a  character- 
istic odor  and  a  nauseous,  bitter  taste.  It  is  poured 
into  skins  which  are  packed  in  cases  for  ship- 
ment. The  variability  of  Socotrine  aloe  probably 
depends  upon  not  only  different  methods  of 
preparation  but  a  different  origin. 

Curacao,  or  West  Indian,  Aloe. — This  aloe, 
which  is  produced  in  the  Dutch  West  Indian 
Islands,  chiefly  in  the  islands  of  Aruba,  Bonaire 
and  Curasao,  appears  not  to  have  entered  com- 
merce extensively  before  the  early  part  of  the 
19th  century,  but  at  present  constitutes  a  very 


large  proportion  of  commercial  aloe.  It  occurs 
chiefly  in  three  forms:  first,  an  opaque,  brittle 
aloe,  showing  abundant  crystals  under  the  micro- 
scope, and  sold  in  gourds  usually  as  Barbados 
aloe;  second,  aloes  having  an  appearance  like  the 
first  variety  but  sold  in  cases;  third,  glossy 
Curagao  or  Capey  Curacao  aloe,  which  occurs  in 
cases  and  is  glossy  and  transparent.  This  variety 
may  become  opaque  upon  long  storage  due  to  the 
gradual  crystallization  of  the  aloin.  Small  frag- 
ments show  a  garnet-red  color. 

Curagao  aloe  is  collected  in  the  Dutch  West 
Indies  by  workers  during  the  early  spring.  The 
leaves  are  cut  off  at  their  bases  and  placed  cut  end 
downward  in  V-shaped  troughs  which  are  arranged 
on  an  incline.  The  juice,  in  trickling  from  the 
leaves,  runs  down  the  sides  of  the  trough  and 
through  an  aperture  at  its  lower  end  into  a  re- 
ceptacle beneath.  As  the  receptacles  are  filled 
with  the  juice,  their  contents  are  poured  into  a 
cask  and  either  evaporated  spontaneously  or  by 
boiling  in  copper  vessels.  As  soon  as  the  juice  has 
thickened  to  the  proper  consistency,  it  is  poured 
into  gourd  shells  or  boxes  and  allowed  to  harden. 
This  aloes  is  shipped  direct  to  the  United  States 
from  Aruba,  Curagao  and  Bonaire. 

Kremel  gives  a  method  to  distinguish  Curagao 
aloe  from  other  kinds  by  adding  to  it  a  little 
cupric  sulfate  solution,  then  some  saturated  solu- 
tion of  common  salt,  which  makes  the  color  an 
intense  carmine.  The  reaction  is  due  to  cupro- 
aloin.  Curagao  aloe,  deprived  of  its  aloin,  has 
occurred  in  the  markets;  this  fraudulent  product 
was  then  sold  as  Cape  aloe;  the  odor  of  the 
Curagao  variety  still  remains. 

Cape  Aloe. — This  variety,  while  chiefly  from 
Aloe  ferox,  is  derived,  at  times,  from  hybrids  of 
this  species  with  Aloe  africana  and  Aloe  spicata. 
The  general  method  of  collecting  Cape  aloe  is  to 
allow  the  juice  in  the  excised  leaves  to  drain  into 
a  canvas  or  goat's  skin,  which  has  been  so  placed 
in  a  hole  in  the  ground  as  to  force  the  juice  to 
collect  in  the  center.  Later  this  juice  is  poured 
into  a  drum  or  tin,  in  which  it  is  boiled  for  4  or 
5  hours  with  constant  stirring  and,  when  suffi- 
ciently concentrated,  poured  into  boxes  or  bar- 
rels and  allowed  to  harden.  In  these  containers 
it  is  shipped  from  Mossel  Bay  and  Port  Eliza- 
beth to  Cape  Town,  thence  to  Europe  and  Amer- 
ica. Cape  aloe  differs  from  Socotrine  aloe,  espe- 
cially in  its  brilliant  conchoidal  fracture  and 
peculiar  odor,  which  is  strong,  but  neither  nau- 
seous nor  aromatic.  When  freshly  broken  it  has  a 
very  dark  olive  or  greenish  color  approaching  to 
black,  presents  a  smooth,  bright,  almost  glassy 
surface,  and  if  held  up  to  the  light  appears  trans- 
lucent at  its  edges.  The  small  fragments  also  are 
semi-transparent,  and  have  a  tinge  of  yellow  or 
red  mixed  with  the  deep  olive  of  the  opaque  mass. 
Cape  aloe,  when  quite  hard,  is  very  brittle  and 
readily  powdered;  but  in  very  hot  weather  it  is 
apt  to  become  somewhat  soft  and  tenacious,  and 
the  interior  of  the  pieces  is  occasionally  more  or 
less  so  even  in  winter. 

Uganda,  or  crown,  aloe  is  a  brand  of  Cape  aloe 
formerly  produced  by  manufacturers  who  bought 
the  aloe  juice  from  the  collectors,  allowed  it  to 
undergo  a  slight  fermentation,  and  dried  it  in  the 


48 


Aloe 


Part  I 


sun  in  wooden  troughs.  It  was  sent  into  com- 
merce in  bags  containing  coarse  or  fine  powder, 
or  chips,  and  in  bricks  wrapped  in  red  paper;  it 
has  a  very  bitter,  aromatic  taste  and  a  strongly 
aromatic  odor.  The  bricks  were  of  a  hepatic 
brown  color,  with  a  resinous  fracture,  which  had 
a  bronzy-gold  luster  by  refracted  light.  Uganda 
aloe  is  now  practically  obsolete. 

An  adulterant  in  powdered  Cape  aloe  is  a 
ferruginous  clay  associated  with  calcium  carbon- 
ate. The  method  of  detecting  this  adulterant  is 
based  on  the  fact  that  pure  Cape  aloe  dissolves  in 
ammonium  hydroxide  solution  diluted  with  nine 
times  its  volume  of  distilled  water.  The  adulterant 
can  be  readily  separated,  and  the  amount  esti- 
mated by  its  insolubility,  Leger  (/.  phartn.  chim., 
1934,  19,  533). 

Other  Varieties. — Besides  the  above  certain 
other  forms  of  aloe  have  appeared  from  time  to 
time  in  commerce.  Barbados  aloe,  which  is  the 
hepatic  sub-variety  of  Curagao  aloe,  appears  to 
have  been  brought  to  London  as  early  as  1693. 
Small  quantities  still  appear  occasionally  on  the 
American  markets.  Barbados  aloe  is  produced 
from  A.  barbadensis. 

Barbados  aloe  which  is  erroneously  recognized 
by  the  B.P.  as  the  same  as  Curasao  aloes,  varies 
in  color  from  very  dark  blackish-brown  through 
reddish-brown  and  liver-colored  to  orange-brown. 
It  yields  a  dull  olive-yellow  powder,  of  a  dis- 
agreeable, even  nauseous  odor,  and  it  was  de- 
scribed in  the  British  Pharmacopoeia  as  follows: 
"Fracture  either  dull  and  waxy,  in  which  case 
small  splinters  are  opaque;  or  smooth  and  glassy, 
in  which  case  the  splinters  are  transparent;  the 
opaque  variety  examined  under  the  microscope 
exhibits  numerous  minute  crystals  embedded  in 
a  transparent  mass."  B.P.,  1898.  "Mixed  with 
nitric  acid,  it  acquires  a  red  color.  Barbados  Aloes 
is  not  colored,  or  acquires  only  a  light  bluish- 
green  tint,  on  being  mixed  with  sulphuric  acid 
and  blowing  the  vapor  of  nitric  acid  over  the 
mixture  (difference  from  Natal  aloe)."  U.S.P., 
1890. 

Natal  aloe  is  a  variety  coming  from  Natal  on 
the  southeast  coast  of  Africa,  the  origin  of  which 
is  not  definitely  ascertained  but  is  possibly  A. 
candelabrum  Berger.  It  occurs  in  irregular,  usually 
opaque  pieces,  with  a  fracture  much  less  shining 
than  that  of  Cape  aloe  and  a  totally  different 
color,  having  a  greenish  slate  hue.  It  yields  a 
grayish-green  or  pale  yellow  powder,  which  has 
the  odor  of  Cape  aloe.  It  is  less  soluble  than 
Cape  aloe. 

When  powdered  Natal  aloe  is  mixed  with  a 
little  sulfuric  acid  and  the  fumes  of  nitric  acid 
are  blown  over  it,  a  deep  blue  coloration  is 
produced. 

Hepatic  aloe,  as  well  as  fetid,  caballine  or  horse 
aloe,  have  no  proper  claim  to  be  considered  dis- 
tinct varieties,  being  simply  inferior  aloe  of 
various  origins,  the  first  liver-colored,  the  second 
blackish  and  fetid  and  full  of  impurities. 

Jafferabad  aloe,  supposed  to  be  the  same  as 
Mocha  aloe,  has  been  shown  to  be  the  product  of 
A.  abyssinica  Lam.,  and  is  said  by  Shenstone  to 
contain  ^-barbaloin.  (Am.  J.  Pharm.,  1883,  92.) 
Aloe  made  in  India  from  the  A.  barbadensis  is 


known  as  Musambra  aloe.  It  appears  to  be  a 
very  inferior  variety,  and  rarely,  if  ever,  reaches 
Europe. 

The  labels  under  which  aloe  is  sold  often  have 
little  or  no  connection  with  the  place  of  produc- 
tion, or  with  the  variety  of  aloes  in  the  package. 
This  fact  has  probably  come  about  through  the 
indifference  of  users  to  the  variety  of  the  aloe 
which  they  are  purchasing,  an  indifference  largely 
due  to  the  common  habit  of  buying  aloe  in 
powder. 

Wilbert  (Am.  J.  Pharm.,  1903)  proposed  that 
aloe  should  be  classified  as  follows:  Aloe  A. — Con- 
taining barbaloin;  responds  to  Borntrager's  test 
for  emodin,  but  does  not  give  a  distinct  red  color 
with  nitric  acid,  or  with  Klunge's  test.  Aloe  B. — 
Containing  isobarbaloin  with  barbaloin;  responds 
to  Borntrager's  test  for  emodin,  and  also  has  a 
deep  red  color  with  strong  nitric  acid,  or  with 
Klunge's  test. 

Fairbairn  (Pharm.  J.,  1946,  102,  381)  has  de- 
scribed the  microscopy  of  the  common  commercial 
varieties  of  aloe. 

In  1952  importations  of  aloe  into  the  United 
States  amounted  to  413,847  pounds,  most  of  it 
from  the  Union  of  South  Africa  and  N.  Antilles, 
although  considerable  came  also  from  the  Do- 
minican Republic  and  Venezuela. 

Description.  —  "Unground  Socotrine  Aloe 
occurs  in  reddish  black  to  brownish  black, 
opaque,  smooth,  glistening  masses.  Its  fractured 
surface  is  somewhat  conchoidal.  It  has  a  char- 
acteristic odor. 

"Unground  Curagao  Aloe  occurs  in  brownish 
black,  opaque  masses.  Its  fractured  surface  is 
uneven,  waxy,  and  somewhat  resinous.  It  has  a 
characteristic,  disagreeable  odor. 

"Unground  Cape  Aloe  occurs  in  dusky  to  dark 
brown  irregular  masses,  the  surfaces  of  which  are 
often  covered  with  a  yellowish  powder.  Its  frac- 
ture is  smooth  and  glassy.  Its  odor  is  character- 
istic, somewhat  sour  and  disagreeable. 

The  taste  of  each  variety  of  Aloe  is  nauseous 
and  very  bitter. 

"Powdered  Aloe  is  yellow,  yellowish  brown  to 
olive  brown  in  color.  When  mounted  in  a  bland 
expressed  oil  it  appears  as  greenish  yellow  to  red- 
dish brown  angular  or  irregular  fragments,  the 
hues  of  which  depend  to  some  extent  upon  the 
thickness  of  the  fragments."  U.S.P. 

Standards  and  Tests. — Identification. — (1) 
Powdered  aloe  dissolves  in  nitric  acid  with  effer- 
vescence; the  solution  is  reddish  brown  to  brown 
or  green.  (2)  The  aqueous  extract  prepared  by 
shaking  1  Gm.  of  finely  powdered  aloe  with  25 
ml.  of  cold  water  during  2  hours,  filtering,  then 
washing  the  filter  and  residue  with  cold  water  to 
yield  100  ml.  of  filtrate  exhibits  the  following 
colors  when  viewed  in  the  bulb  of  a  100  ml.  volu- 
metric flask:  dark  yellow  with  Socotrine  aloe, 
dark  orange  with  Curagao  aloe,  and  greenish  yel- 
low with  Cape  aloe.  The  filtrate  darkens  on  stand- 
ing. (3)  Addition  of  2  ml.  of  nitric  acid  to  5  ml. 
of  the  filtrate  from  test  (2)  produces  the  follow- 
ing colors:  yellow  with  Socotrine  aloe,  reddish 
orange  with  Curagao  aloe,  and  a  reddish  brown 
changing  rapidly  to  green  with  Cape  aloe.  (4) 
Addition  of  45  ml.  of  water  and  20  ml.  of  a  1  in 


Part  I 


Aloe 


49 


20  solution  of  sodium  borate  to  5  ml.  of  the 
filtrate  from  test  (2)  produces  a  greenish  yellow 
or  yellowish  green  fluorescence  which  on  standing 
turns  to  a  moderate  yellowish  orange  to  brown 
color.  Water. — Not  over  12  per  cent,  when  dried 
at  105°  for  5  hours.  Ash. — Not  over  4  per  cent. 
Alcohol-insoluble  matter. — Not  over  10  per  cent, 
when  1  Gm.  of  powdered  aloe  is  extracted  with 
50  ml.  of  boiling  alcohol,  the  residue  being  dried 
to  constant  weight  at  105°.  U.S. P. 

Rosenthaler  (Pharm.  Acta.  Helv.,  1937,  12, 
96)  proposed  two  tests  for  aloe:  (1)  An  aqueous 
solution  of  aloe  is  heated  with  sodium  hydroxide 
and  ammonium  sulfide;  Cape  aloe  or  Barbados 
aloe  turns  green  or  greenish  brown,  Natal  aloe 
brown.  The  reaction  is  given  by  both  aloin  and 
barbaloin.  (2)  A  solution  of  aloe  is  heated  with 
sodium  hydroxide  and  an  ammonium  salt:  Bar- 
bados aloe  gives  a  purple  color,  Natal  a  bluish- 
purple,  Cape  aloe  does  not  react.  The  reaction  is 
a  test  for  isobarbaloin. 

Keenan  and  Welsh  (/.  A.  Ph.  A.,  1942,  31,  535) 
reported  that  a  5  per  cent  solution  of  gold  chloride 
gave  superior  results  to  the  other  commonly  used 
microchemical  agents  with  barbaloin  and  isobar- 
baloin, and  suggest  its  use  in  distinguishing  dif- 
ferent varieties  of  aloe.  With  Curasao  aloe  it  gave 
an  immediate  red  color,  with  Cape  aloe  a  green, 
while  Socotrine  aloe  remained  brown.  For  other 
tests  for  distinguishing  varieties  of  aloes  see 
Allen's  Commercial  Organic  Analysis,  Volume  8, 
Fifth  Edition  (1930). 

Assay.— Determine  the  per  cent  of  water-sol- 
uble extractive.  U.S.P.  The  B.P.  requires  not  less 
than  75.0  per  cent  of  water-soluble  extractive, 
calculated  with  reference  to  the  air-dried  drug. 

Various  methods  of  assaying  aloe,  utilizing  a 
determination  of  the  content  of  aloin,  have  been 
proposed.  Goldner  (/.  A.  Ph.  A.,  1932,  21,  658) 
concluded  that  none  of  the  seven  methods  he  in- 
vestigated was  satisfactory.  Eaton  (J.A.O.A.C., 
1932,  15,  407)  devised  a  method  in  which  the 
aloin  is  acetylized  to  aloin  hexa-acetate  and 
weighed  in  this  form;  the  method  is  officially 
recognized  in  the  A.O.A.C.  Methods  of  Analysis. 
Valaer  and  Mallory  (Am.  J.  Pharm.,  1934,  106, 
81)  proposed  that  aloe  and  its  preparations  be 
assayed  by  determining  the  free  emodin  and  the 
total  emodin  content;  their  method  is  based  on  a 
measurement  of  the  depth  of  color  produced  by 
emodin  in  a  strongly  alkalinized  solution. 

Constituents. — The  chemistry  of  aloe  is  in- 
completely known.  It  is  generally  believed  that 
aloe  owes  its  purgative  properties  to  the  presence 
of  one  or  more  of  three  pentosides  known  as  bar- 
baloin (aloin),  isobarbaloin  and  beta-barbaloin. 
For  lack  of  satisfactory  assay  methods  the  con- 
tent of  these  constituents  is  not  known  with  any 
degree  of  certainty  (see  under  Aloin).  Viehoever 
(Am.  J.  Pharm.,  1935,  107,  47)  considers  the 
resin  fraction  of  aloe  to  be  of  equal  importance, 
a  view  previously  expressed  by  Kiefer  (Pharm. 
Ztg.,  1925,  70,  1775).  Chopra  and  Ghosh  (Arch. 
Pharm.,  1938,  276,  348)  reported  that  A.  vera 
var.  officinalis  (A.  indica)  contains  no  aloin. 

Of  the  three  pentosides,  barbaloin  (which  is 
probably  identical  with  the  substances  previously 
described  as  socaloin  and  capaloin)  is  the  most 


important.  It  crystallizes  in  the  form  of  pale 
yellow  needles.  Isobarbaloin  is  isomeric  with  bar- 
baloin; the  former  remains  in  the  mother  liquor 
when  barbaloin  is  crystallized  from  methanol 
solution;  the  two  compounds  also  give  different 
color  reactions  (see  above).  Beta-barbaloin  is  a 
non-crystallizable  optical  isomer  of  barbaloin. 
Hydrolysis  of  barbaloin  in  acid  solution  gives  a 
complex  mixture  in  which  aloe-emodin  (1,8- 
dihydroxy-3-(hydroxymethyl)anthraquinone)  and 
D-arabinose  have  been  identified.  Leger  (Bull.  soc. 
chim.,  1936  [5],  3,  435)  believes  barbaloin  is  an 
ether  formed  by  the  condensation  of  D-arabinose 
with  aloe-emodin,  but  objections  to  this  formula- 
tion have  been  raised  by  Rosenthaler  (Pharm. 
Acta.  Helv.,  1934,  9,  9)  and  by  Foster  and  Gard- 
ner (J.A.C.S.,  1936,  58,  597).  For  data  on  the 
hydrolysis  of  the  aloins  see  Gardner  and  Camp- 
bell (J.A.C.S.,  1942,  64,  1378).  Brody  et  al. 
(J.  A.  Ph.  A.,  1950,  39,  666)  isolated  from 
Curacao  aloe,  by  chromatographic  methods,  aloe- 
emodin,  isoemodin  (3,5,8-trihydroxy-2-methyl- 
anthraquinone),  and  anthranols,  which  are  re- 
ported to  exist  both  in  the  free  state  and  in 
glycosidal  combination. 

Uses. — Aloe  was  known  to  the  ancients,  being 
cultivated  in  the  island  of  Socotra  as  far  back 
as  the  time  of  Alexander  the  Great,  and  is  men- 
tioned in  the  works  of  Dioscorides  and  of  Celsus. 
It  has  been  employed  for  eczematous  skin  condi- 
tions in  China,  India  and  Tibet  under  the  names 
lu  hid,  musabbar  and  jelly  leeks  respectively  (Cole 
and  Chen,  Arch.  Dermat.  Syph.,  1943,  47,  250). 
Its  cathartic  action  is  due  to  a  stimulation  of 
peristalsis,  especially  in  the  larger  bowel,  prob- 
ably the  result  of  a  local  irritant  effect  upon  the 
mucous  membrane,  although  there  is  some  evi- 
dence that  it  exercises  a  specific  stimulant  effect 
upon  unstriped  muscles;  considerable  griping  pain 
is  often  associated  with  its  action.  It  is  more  irri- 
tating than  cascara  sagrada,  senna  and  rhubarb. 
As  its  action  is  largely  limited  to  the  colon  it  is 
not  to  be  recommended  in  those  conditions  in 
which  it  is  desirable  to  clean  out  the  whole  ali- 
mentary canal,  and  as  its  effect  is  largely  the  result 
of  local  irritation  it  should  be  avoided  in  inflam- 
matory conditions  of  the  intestine.  It  does  not 
act  until  8  to  12  hours  after  ingestion.  In  chronic 
constipation,  especially  when  dependent  upon  an 
atonic  condition  of  the  lower  bowel,  it  is  very 
useful.  The  presence  of  bile  in  the  bowel  seems 
to  be  essential  for  the  most  effective  action  of 
this  drug,  and  when  this  secretion  is  lacking  it  is 
advisable  to  administer  some  preparation  of  bile 
in  conjunction  with  the  aloes.  Soap  also  appears 
to  enhance  the  cathartic  action  of  this  drug.  Ivy 
and  his  associates  (Quart.  Bull.  Northwest.  U. 
Med.  Sch.,  1945,  19,  102)  reported  that  thera- 
peutic doses  of  aloe  produce  no  increase  in  the 
bile  content  of  the  intestine.  Aloe  was  formerly 
used  in  the  treatment  of  amenorrhea.  It  is,  how- 
ever, extremely  doubtful  whether  it  exercises  any 
action  on  the  pelvic  organs  other  than  congestion 
of  the  pelvic  blood  vessels. 

In  the  16th  and  17th  centuries  aloe  was  used 
locally  in  the  treatment  of  wounds  and  burns 
but  its  use  for  this  purpose  entirely  disappeared 
except   as   an  ingredient   in   compound   benzoin 


50 


Aloe 


Part   I 


tincture.  Collins  and  Collins  (Am.  J.  Roentgen., 
1935,  33,  396)  reported  beneficial  effects  from  the 
local  application  of  freshly  split  leaves  of  the 
Aloe  vera  in  the  treatment  of  x-ray  burns.  After 
an  hour  of  contact  the  darkened  gummy,  gelati- 
nous material  was  washed  away  with  water.  (See 
also  Lovemna.  Arch.  Dermat.  Syph.,  1937,  36, 
838.)  Crewe  (Minn.  Med.,  1937,  20,  10)  extended 
this  local  use  of  aloe  leaf  to  the  treatment  of 
dermatitis  and  various  ulcerated  conditions  of 
the  skin.  Rowe  and  colleagues  (/.  A.  Ph.  A.,  1941, 
30,  266),  in  an  experimental  study  of  aloe  leaf 
in  x-ray  burns,  found  that  the  curative  principle 
occurs  in  both  the  pulp  and  rind  of  the  leaf,  but 
was  not  present  in  all  commercial  leaves  nor  in 
the  official  aloe.  Cutaneous  leishmaniasis  was 
benefited  by  injections  of  an  extract  of  aloe 
leaves  (Filatov,  Am.  Rev.  Soviet  Med.,  1945.  2, 
484).  E 

Dose. — Aloe  is  today  infrequently  adminis- 
tered; its  usual  dose  is  250  mg.  (approximately 
4  grains),  with  a  fange  of  120  to  250  mg. 

Aloe  Tincture,  prepared  by  macerating  10 
per  cent  w/v  of  aloe  and  20  per  cent  w/v  of 
glycyrrhiza  with  diluted  alcohol,  was  official  in 
N.F.IX.  Aloe  Pills,  made  by  massing  a  mixture 
of  equal  parts  of  aloe  and  hard  soap  with  water, 
were  also  official  in  N.F.IX. 

Off.  Prep. — Compound  Benzoin  Tincture, 
U.S.P.,  B.P.;  Compound  Colocynth  Extract,  N.F. 

ALOIN.     X.F.,  B.P. 

[Aloinum] 

"Aloin  is  a  mixture  of  active  principles  ob- 
tained irom  aloe.  It  varies  in  chemical  compo- 
sition and  in  physical  and  chemical  properties 
according  to  the  variety  of  aloe  from  which  it 
is  obtained."  N.F.  The  B.P.  defines  it  as  a  mix- 
ture of  crystalline  principles  obtained  from  aloes. 

Sp.  Aloina. 

Aloin,  which  consists  principally  of  barbaloin 
and  isobarbaloin  (see  under  Aloe),  has  been  pre- 
pared by  many  processes.  That  recommended 
by  Tilden  is  as  follows:  1  part  of  aloe  is  dis- 
solved in  10  parts  of  boiling  water  acidulated 
with  hydrochloric  acid,  and  allowed  to  cool.  The 
liquid  is  then  decanted  from  resinous  matter, 
evaporated  to  about  2  parts,  and  set  aside  two 
weeks  for  crystals  to  form;  the  liquid  portion  is 
poured  off,  the  crystals  pressed,  and  the  adherent 
resinous  matter  separated  by  shaking  with  etnyl 
acetate,  which  dissolves  the  resin.  This  process 
serves  fairly  well  for  obtaining  aloin  from  Bar- 
bados or  Curagao  aloe.  Aloin  from  Socotrine  aloe 
is  best  obtained  by  digesting  it  in  3  parts  of 
alcohol  for  24  hours,  then  transferring  to  a  water 
bath,  and  boiling  for  2  hours.  After  cooling,  the 
liquid  is  filtered  and  set  aside  to  crystallize.  The 
crystals  are  washed  with  alcohol  and  dried.  The 
yield  is  about  10  per  cent.  Schafer  (Pharm.  J., 
1897,  p.  287)  obtained  from  15  to  30  per  cent  of 
crystallized  aloin  from  commercial  aloe  by  the 
following  process:  50  Gm.  of  aloe  dissolved  in 
300  ml.  of  hot  water  is  slightly  acidulated  with 
hydrochloric  acid.  The  solution,  after  standing 
(for  the  resins  to  separate),  is  decanted,  mixed 


with  50  ml.  of  20  per  cent  ammonia  water,  fol- 
lowed by  a  solution  of  15  Gm.  of  calcium  chloride 
in  30  ml.  of  water.  The  liquid  is  agitated  and  the 
aloin-calcium  compound  which  separates  is  col- 
lected, drained,  and  mixed  in  a  mortar  with  a 
slight  excess  of  hydrochloric  acid;  the  mixture  of 
aloin  and  calcium  chloride  is  dissolved  in  the 
smallest  possible  quantity  of  boiling  water,  fil- 
tered, and  the  filtrate  cooled  by  means  of  ice; 
the  aloin  crystallizes.  This  method  was  recom- 
mended by  Snyder  as  a  procedure  for  evaluating 
aloe  (see  Viehoever,  Am.  J.  Pharm.,  1935,  107, 
58)  and  was  found  by  Smith,  Jordan  and  De  Kay 
(/.  A.  Ph.  A.,  1944,  33,  57;  to  be  best  adapted 
for  extracting  aloin  in  the  assay  of  Barbados  and 
Curasao  aloe.  For  chemistry  of  aloin,  see  under 
Aloe. 

Description. — "Aloin  occurs  as  a  lemon  yel- 
low to  dark  yellow,  microcrystalline  powder,  or 
as  minute  crystals.  It  is  odorless,  or  has  a  slight 
odor  of  aloe.  Its  taste  is  intensely  bitter.  Aloin 
darkens  on  exposure  to  fight  and  air.  A  saturated 
solution  of  Aloin  is  yellow  but  becomes  brown 
on  standing.  Its  solutions  are  neutral  or  acid  to 
litmus  paper.  Aloin  is  soluble  in  water,  in  alcohol, 
and  in  acetone,  the  degree  of  solubility  varying 
with  its  composition.  It  is  slightly  soluble  in 
ether."  N.F. 

Standards  and  Tests. — Identification. — (1) 
Aloin  dissolves  in  ammonia  T.S.  and  in  alkali 
hydroxide  solutions  with  formation  of  a  red  color 
(or  yellow  turning  to  red)  and  a  green  fluores- 
cence. (2)  A  brownish  green  color  results  when 
a  drop  of  ferric  chloride  T.S.  is  added  to  an 
alcohol  solution  of  aloin.  Residue  on  ignition. — 
Not  over  0.6  per  cent.  Water-insoluble  sub- 
stances.— Not  over  1.5  per  cent  of  residue  is  ob- 
tained when  1  Gm.  of  aloin  is  agitated  during 
2  hours  with  120  ml.  of  water,  at  25°,  the  insoluble 
matter  being  collected  on  a  filter  paper  or  in  a 
filtering  crucible,  washed  with  25  ml.  of  water, 
and  dried  at  105°  for  1  hour  prior  to  weighing. 
Emodin. — Xot  more  than  a  faint,  pink  color 
results  when  the  filtrate  from  a  1  in  10  benzene 
extract  of  aloin  is  shaken  with  an  equal  volume 
of  a  5  per  cent  solution  of  ammonia.  N.F. 

Aloin  of  commerce  has  been  frequently  con- 
taminated with  large  amounts  of  resin,  indicat- 
ing lack  of  care  in  manufacturing.  The  N.F.  test 
for  water-insoluble  substances  limits  the  amount 
of  such  contamination  to  1.5  per  cent.  Smith 
et  al.  (J.  A.  Ph.  A.,  1944,  33,  59)  called  atten- 
tion to  the  fact  that  aloins  from  different  species 
of  aloe  give  different  reactions  in  the  various 
color  tests. 

Uses. — Because  of  the  absence  of  resin  the 
cathartic  action  of  aloin  is  relatively  milder  than 
that  of  aloe.  Although  it  is  capable  of  producing 
purgative  effects,  it  is  never  used  practically  in 
this  manner.  Aloin  has  enjoyed  wide  use  in 
chronic  constipation.  It  is  often  combined  with 
belladonna  to  overcome  the  tendency  to  griping. 
However,  the  action  of  belladonna  is  rapid  and 
brief  compared  with  that  of  aloin.  Aloin  may  pro- 
duce renal  irritation  and  color  the  urine  red  if 
the  latter  is  alkaline.  S 

Dose,  10  to  60  mg.  (approximately  %  to  1 
grain). 


Part  I 


Alum 


51 


Storage. — Preserve  "in  tight,  light-resistant 
containers."  N.F. 

Off.  Prep. — Aloin,  Belladonna,  Cascara  and 
Podophyllum  Pills.  N.F. 

ALOIN,    BELLADONNA,    CASCARA 
AND  PODOPHYLLUM  PILLS.     N.F. 

Hinkle's  Pills,  [Pilulae  Aloini,  Belladonna, 
Cascarae  et  Podophylli] 

Prepare  100  pills,  according  to  the  General 
Directions  (see  under  Pills),  from  1.6  Gm.  of 
cascara  sagrada  extract,  1.6  Gm.  of  aloin,  1  Gm. 
of  podophyllum  resin,  0.8  Gm.  of  belladonna  ex- 
tract, 0.4  Gm.  of  ginger  oleoresin,  and  1  Gm.  of 
glycyrrhiza,  in  fine  powder,  using  liquid  glucose 
as  the  excipient.  N.F. 

Dose,  as  a  laxative,  one  or  two  pills. 

ALTHEA.     N.F. 

Marshmallow  Root,   [Althaea] 

"Althea  is  the  dried  root  of  Althcea  officinalis 
Linne  (Fam.  Malvaceae),  deprived  of  the  brown, 
corky  layer  and  small  roots."  N.F. 

White  Mallow.  Radix  Bismalvae;  Radix  Hibisci.  Fr. 
Guimauve ;  Racine  de  guimauve.  Ger.  Eibischwurzel ;  Bis- 
malvawurzel;  Altheewurzel;  Heilwurzel.  It.  Altea;  Mal- 
vischio;   Malvaccioni.  Sp.   Raiz  de  altea;   Altea. 

Althcea  officinalis  is  a  perennial  herb  with  a 
perpendicular  branching  root  and  erect  woolly 
stems,  from  two  to  four  feet  or  more  in  height, 
branched  and  leafy  toward  the  summit.  The 
plant  is  native  to  Europe,  inhabiting  salt  marshes, 
the  banks  of  rivers,  and  other  moist  places.  It  is 
found  also  in  this  country,  from  New  England  to 
New  York  and  westward  to  Michigan  and  Arkan- 
sas. It  is  largely  cultivated  in  Europe  for  medici- 
nal use. 

The  roots  should  be  collected  in  autumn  from 
plants  at  least  two  years  old.  They  are  usually 
prepared  for  the  market  by  removing  the  rootlets, 
scraping  the  roots  free  of  cork  and  drying  either 
entire  or  after  slicing  the  thicker  roots. 

Description. — "Unground  Althea. — When  en- 
tire, Althea  occurs  as  slenderly  tapering  roots,  up 
to  30  cm.  in  length  and  2  cm.  in  diameter;  exter- 
nally pale  yellow  to  pale  brown,  longitudinally 
furrowed,  frequently  spirally  twisted  and  covered 
with  somewhat  loosened  bast  fibers.  The  fracture 
of  the  bark  is  fibrous,  and  of  the  wood,  short  and 
granular.  Internally  it  is  yellowish;  the  bark  is 
1  to  2  mm.  thick,  porous,  with  mucilage  cells  and 
is  separated  from  the  slightly  radiating  wood  by 
a  distinct  darker  cambium  zone.  Althea  is  fre- 
quently cut  into  small  pieces  about  5  mm.  in 
thickness.  Sometimes  the  root  is  found  split  or 
in  slices.  Althea  has  a  slight  odor  and  a  sweetish, 
mucilaginous  taste."  N.F.  For  histology  see  N.F.  X. 

"Powdered  Althea  is  white  to  weak  yellow.  It 
consists  of  numerous  starch  grains  up  to  30  n  in 
diameter,  usually  with  a  long  central  cleft;  groups 
of  fibers  with  thick,  more  or  less  lignified  walls; 
vessels  with  scalariform  thickenings  or  with  bor- 
dered pits,  and  a  few  calcium  oxalate  crystals  in 
rosette  aggregates,  from  20  to  35  (x  in  diameter." 
N.F. 

Standards  and  Tests.— Identification.— The 
mucilage  obtained  by  stirring  a  mixture  of  1  Gm. 


of  comminuted  althea  with  10  ml.  of  cold  distilled 
water  during  30  minutes,  then  filtering  through 
cotton,  has  a  weak  yellow  color  and  is  only 
slightly  acid  to  litmus;  on  addition  of  sodium 
hydroxide  T.S.  it  assumes  a  moderate  to  strong 
yellow  color,  and  has  neither  a  sour  nor  an  am- 
moniacal  odor.  Foreign  organic  matter. — Not  over 
1  per  cent.  Acid-insoluble  ash. — Not  over  1  per 
cent.  N.F. 

Constituents. — Althea  contains  on  the  aver- 
age 37  per  cent  of  starch,  35  per  cent  of  gum,  11 
per  cent  of  pectin,  11  per  cent  of  sugar,  1.25  per 
cent  of  fat  and  up  to  2  per  cent  of  asparagin. 

The  principle,  discovered  in  the  root  by  Bacon, 
by  him  called  althein,  has  been  found  to  be 
asparagin.  This  substance  belongs  to  the  group 
of  amides  and  hence  has  been  called  asparamide, 
also  aspargine  and  agedoite.  It  is  a-aminosuccin- 
amic  acid,  NH2COCH2.CH(NH2)COOH.  When 
treated  with  a  strong  acid  it  yields  aminosuccinic 
(aspartic)  acid  which  is  also  a  product  of  pancre- 
atic digestion  of  certain  proteins.  Asparagin  is 
found  in  many  other  plants  but  is  of  no  medicinal 
importance. 

Under  the  title  of  Althcece.  Folia  (Marsh  Mal- 
low Leaves),  the  N.F.  V  recognized  the  dried 
leaves  of  the  Althcea  officinalis  collected  in  June 
or  July,  while  the  plant  is  in  flower,  and  dried. 
They,  like  the  root,  have  been  used  for  their  muci- 
lage, which  is,  however,  less  abundant  in  the 
leaves.  For  a  description  of  the  leaves,  see  U.S.D., 
22nd  ed.,  p.  108. 

The  N.F.  IX  recognized  Althea  Syrup,  which 
has  been  used  as  a  demulcent  vehicle.  It  was  pre- 
pared as  follows :  Wash  50  Gm.  of  althea,  cut  into 
small  pieces,  with  cold  distilled  water.  Macerate 
this  with  a  mixture  of  400  ml.  of  distilled  water 
and  30  ml.  of  alcohol  for  3  hours  at  room  tempera- 
ture, without  stirring;  strain  the  mixture  without 
expressing  the  residue,  dissolve  in  the  strained 
liquid,  by  agitation  and  without  heat,  700  Gm.  of 
sucrose.  Add  100  ml.  of  glycerin  and  enough  water 
to  make  1000  ml. 

Uses. — The  virtues  of  marshmallow  are  exclu- 
sively those  of  a  demulcent.  The  decoction  of  the 
root  has  been  much  used  in  Europe  in  irritation 
and  inflammation  of  the  mucous  membranes.  The 
roots  themselves,  as  well  as  the  leaves  and  flowers, 
boiled  and  bruised,  have  been  employed  as  a 
poultice.  Althea  also  finds  use  as  an  excipient  for 
pills. 

Off.  Prep.— Ferrous  Carbonate  Pills,  N.F. 

ALUM.     N.F.,  B.F. 

Ammonium  Alum,  Potassium  Alum,   [Alumen] 

"Alum  contains  not  less  than  99.5  per  cent  of 
AlNH4(S04)2.12HoO  or  of  A1K(S04)2.12H20. 
The  label  of  the  container  must  indicate  whether 
the  salt  is  Ammonium  Alum  or  Potassium  Alum." 
N.F.  The  B.P.  definition  is  essentially  the  same 
and  the  purity  rubric  is  identical  with  that  of 
the  N.F. 

Purified  Alum.  Alumen  Purificatum.  Sp.  Alumbre. 

The  term  alum  is  a  generic  name  for  a  group 
of  double  salts  of  the  general  formula: 
R2S04.R,2(S04)3.24H20,  or  RR'(S04)2.12H20 


52 


Alum 


Part  1 


in  which  R  is  univalent  and  may  be  Na,  K,  Rb, 
Cs,  etc.,  or  a  radical  such  as  NH4,  and  R'  is 
trivalent  and  may  be  Fe,  Cr,  Al,  etc.  Alums 
have  been  prepared  in  which  SeOi,  or  TeCh,  have 
replaced  SO-t. 

The  alum  officially  recognized  may  be  either 
the  double  sulfate  of  aluminum  and  potassium,  or 
of  aluminum  and  ammonium.  These  are  distin- 
guished as  potassium  alum  and  ammonium  alum, 
respectively.  From  time  to  time  one  or  the  other 
of  these  has  been  given  official  preference,  but 
at  present  both  are  recognized  under  the  common 
title  of  Alum  in  the  official  compendia  of  the 
United  States  and  of  Great  Britain. 

Potassium  Alum.  Potassium  Aluminum  Sul- 
fate. Aluminii  et  Potassii  Sulfas;  Fr.  Alun  de 
potassium;  Alun;  Sulfate  double  d'alumina  et 
de  potasse.  Ger.  Alaun;  Kaliumalaun.  It.  Allume 
di  potassa;  Allume;  Allume  di  rocca.  Sp.  Sulfato 
de  aluminio  y  de  potasio ;  Alumbre. — Alum  has 
been  manufactured  for  centuries,  the  chemical 
having  been  used  in  the  time  of  Pliny  as  a  mor- 
dant for  the  production  of  bright  colors.  It  may 
be  obtained  from  several  natural  sources,  among 
which  the  more  important  are  the  minerals  alu- 
nite,  bauxite  and  cryolite. 

Al  unite  (or  alum  stone),  a  mixture  of  alumi- 
num sulfate  and  potassium  sulfate,  is  subjected 
to  a  roasting  process,  by  which  is  formed  alum 
and  insoluble  alumina.  Upon  treatment  with  sul- 
furic acid,  the  alumina  passes  into  solution  as 
aluminum  sulfate;  this  may  be  recovered  from 
the  mother  liquors  after  crystallization  of  the 
alum,  or  potassium  sulfate  may  be  added  in  suf- 
ficient quantity  to  convert  the  aluminum  sulfate 
to  alum.  . 

Bauxite,  a  hydrated  oxide  of  aluminum  con- 
taining from  30  to  76  per  cent  of  aluminum  oxide, 
has  become  an  important  source  of  alum.  Alumi- 
num sulfate  obtained  from  this  mineral  is  treated, 
in  solution,  with  potassium  sulfate  and  the  alum 
obtained  by  crystallization.  Cryolite,  a  double 
fluoride  of  sodium  and  aluminum,  also  serves  as 
a  source  of  aluminum  salts,  from  which  can  be 
made  also  the  alums.  Various  earths  and  clays, 
known  as  aluminous  schist,  alum  slate,  and  alum 
shale  furnish  other  sources  of  alum. 

Potassium  alum  usually  crystallizes  in  octahe- 
dral crystals  having  a  specific  gravity  of  1.75. 
When  heated  to  92.5°,  it  forms  a  solution  in  its 
water  of  crystallization;  continued  heating  vola- 
tilizes the  water,  leaving  behind  a  white,  opaque, 
porous  mass  which  is  the  official  exsiccated  alum 
(see  Exsiccated  Alum).  Exposed  to  high  heat,  it  is 
converted  to  a  mixture  of  aluminum  oxide  and 
potassium  sulfate. 

Ammonium  Alum.  Ammonium  Aluminum 
Sulfate.  Alumen  Ammoniatum;  Aluminii  et 
Ammonii  Sulfas;  Fr.  Alun  d 'ammonium.  Ger. 
Ammonium-alaun ;  Ammoniak alaun.  It.  Allume 
di  ammonio.  Sp.  Sulfato  de  aluminio  y  de  amonio. 
— The  preparation  of  ammonium  alum  is  analo- 
gous to  that  of  potassium  alum.  A  solution  of  alu- 
minum sulfate,  prepared  by  any  of  the  several 
methods  previously  described,  is  treated  with  an 
equivalent  amount  of  ammonium  sulfate.  Upon 
concentration,  crystals  of  ammonium  alum  sepa- 


rate, and  these  may  be  purified  by  recrystalliza- 
tion.  In  crystalline  structure  and  general  physical 
appearance  it  resembles  closely  potassium  alum. 
and  it  is  necessary  to  apply  chemical  tests  to 
differentiate  the  two. 

Ammonium  alum  forms  crystals  similar  to 
those  of  potassium  alum,  and  having  a  specific 
gravity  of  1.63.  When  heated,  ammonium  alum 
swells  up  and  forms  a  porous  mass,  as  water  and 
sulfuric  acid  are  evolved;  continued  ignition  at 
high  temperature  leaves  a  residue  of  aluminum 
oxide. 

Description. — "Alum  occurs  as  large,  color- 
less crystals,  crystalline  fragments,  or  as  a  white 
powder.  Alum  is  odorless,  and  has  a  sweetish, 
strongly  astringent  taste.  Its  solutions  are  acid  to 
litmus  paper.  One  Gm.  of  Ammonium  Alum  dis- 
solves in  7  ml.  of  water,  and  in  about  0.3  ml.  of 
boiling  water.  One  Gm.  of  Potassium  Alum  dis- 
solves in  7.5  ml.  of  water,  and  in  about  0.3  ml.  of 
boiling  water.  Alum  is  insoluble  in  alcohol.  It 
is  freely  but  slowly  soluble  in  glycerin."  N.F. 

Standards  and  Tests. — Identification. — (1) 
Ammonia  is  evolved  and  a  precipitate,  soluble  in 
an  excess  of  reagent,  formed  when  sodium  hydrox- 
ide T.S.  is  added  to  a  1  in  20  solution  of  am- 
monium alum.  (2)  When  potassium  alum  is  simi- 
larly tested  no  ammonia  is  evolved.  (3)  A  violet 
color  is  imparted  by  potassium  alum  to  a  non- 
luminous  flame.  (4)  A  white,  crystalline  precipi- 
tate forms  within  30  minutes  on  adding  10  ml.  of 
sodium  bitartrate  T.S.  to  5  ml.  of  a  saturated 
solution  of  potassium  alum.  (S)  A  1  in  20  solu- 
tion of  alum  responds  to  tests  for  aluminum  and 
for  sulfate.  Alkalies  and  alkaline  earths.— 'Sot 
over  5  mg.  of  residue  is  obtained  on  evaporating 
the  filtrate  from  1  Gm.  of  alum  dissolved  in 
100  ml.  of  water  and  precipitated  with  ammonia. 
Arsenic. — A  solution  of  alum  meets  the  require- 
ments of  the  test  for  arsenic.  Heavy  metals. — The 
limit  is  20  parts  per  million.  Iron — Xo  blue  color 
is  produced  immediately  on  adding  5  drops  of 
potassium  ferrocyanide  T.S.  to  20  ml.  of  a  1  in 
150  solution  of  alum.  N.F. 

The  B.P.  states  that  when  heated  alum  melts 
and  at  about  200°  loses  its  water  of  crystalliza- 
tion. The  presence  of  ammonium  salts  in  potash 
alum  is  detected  with  alkaline  potassium  mercui- 
iodide;  the  arsenic  limit  for  both  alums  is  4  parts 
per  million.  Otherwise  the  tests  are  similar  to 
those  of  the  N.F. 

Assay. — A  sample  of  about  1  Gm.  of  alum  is 
dissolved  in  distilled  water,  ammonium  chloride 
is  added,  and  the  aluminum  is  precipitated  as  hy- 
drous oxide  (hydroxide)  by  the  addition  of  a 
slight  excess  of  ammonia.  The  precipitate  is  fil- 
tered off,  washed,  dried  and  ignited  to  AI2O3; 
the  weight  is  multiplied  bv  8.894  to  obtain  the 
weight  of  A1NH4(S04)2.12H20.  or  by  9.307  to 
obtain  the  weight  of  A1K(S04)2.12H20.  To 
guard  against  the  possibility  of  adding  enough 
ammonia  to  redissolve  a  portion  of  the  hydrous 
aluminum  oxide  precipitate,  the  otherwise  similar 
B.P.  assay  employs  methyl  red  as  an  indicator  to 
limit  the  concentration  of  ammonia. 

Incompatibilities. — Alum  has  the  character- 
istic incompatibilities  of  aluminum  salts  and  of 


Part  I 


Alum,   Exsiccated 


53 


the  sulfates.  In  alkaline  solution,  unless  the  con- 
centration of  hydroxyl  ion  is  sufficiently  high  to 
form  soluble  metaluminate  ion,  aluminum  hy- 
droxide is  precipitated.  Fixed  alkalies  liberate 
ammonia  from  the  ammonium  alum. 

Uses. — Alum  is  absorbed  from  the  intestinal 
tract  only  in  relatively  small  quantities,  although 
Gies  (J. A.M. A.,  1911,  57,  57)  has  shown  that  the 
former  view  that  it  was  completely  excreted,  un- 
absorbed,  with  the  feces  is  incorrect.  The  anti- 
septic power  of  alum  is  lower  than  that  of  most 
salts  of  aluminum;  according  to  Miquel  it  will 
inhibit  the  multiplication  of  bacteria  in  the  pro- 
portion of  about  one  part  in  two  hundred. 

Alum  is  a  powerful  astringent  with  very  de- 
cided irritant  qualities,  and  when  taken  inter- 
nally in  sufficient  quantities  is  emetic  and  pur- 
gative, and  may  even  cause  gastrointestinal  in- 
flammation. It  is  rarely  used  as  an  internal 
astringent.  It  has  been  occasionally  employed 
internally  in  the  treatment  of  lead  colic,  as  a 
chemical  precipitant  of  lead  in  the  intestinal  tract; 
it  was  thought  also  to  have  some  beneficial  action 
upon  the  intestines  directly.  It  is  occasionally  em- 
ployed as  an  emetic  to  empty  the  stomach  in  cases 
of  poisoning,  but  is  inferior  for  this  purpose  to 
zinc  sulfate.  It  was  formerly  extensively  used  as  a 
gargle,  but  it  exercises  a  destructive  influence 
upon  the  teeth  and  is  inferior  to  aluminum  acetate. 

The  most  important  use  of  alum  today  is  as  a 
local  astringent  to  check  excessive  local  sweating 
or  to  harden  the  skin,  especially  of  the  feet.  Po- 
tassium alum  in  10  per  cent  aqueous  solution  is 
efficient  in  removing  flora  from  normal  skin,  but 
less  so  than  alcohol  or  0.5  per  cent  hydrochloric 
acid  according  to  Myer  and  Vicher  (Arch.  Surg., 
1943,  47,  468).  Such  a  solution  hardens  the  skin, 
imprisoning  bacteria  which  may  be  released  as  the 
skin  softens  when  covered  by  rubber  gloves.  It  is 
also  employed  as  an  astringent  in  leukorrhea.  un- 
healthy ulcers,  and  similar  conditions.  As  an 
astringent  it  is  usually  employed  in  strengths 
ranging  from  1  to  5  per  cent,  according  to  the 
location  to  which  it  is  applied.  Occasionally  pow- 
dered alum  may  be  thinly  dusted  over  the  area. 
As  a  styptic  it  is  employed  as  an  alum  stick  or  as 
the  powdered  chemical  and  applied  directly  to 
the  bleeding  point  if  easily  accessible.  In  epistaxis 
the  nares  may  be  plugged  with  pledgets  of  cotton 
soaked  in  a  saturated  solution.  When  used  as  an 
astringent  on  the  more  delicate  mucous  mem- 
branes, as  in  conjunctivitis,  it  is  desirable  to 
modify  its  action  by  combining  it  with  albuminous 
matter  as  in  the  form  of  the  alum  curd.  This  is 
made  by  boiling  8  Gm.  of  alum  in  480  ml.  of 
milk  and  straining  off  the  whey.  Concentrations 
with  effective  spermicidal  action  (0.5  to  1  per 
cent)  are  uncomfortably  astringent,  [vj 

Toxicology. — When  taken  in  large  dose, 
alum  acts  as  an  irritant  poison  causing  burning 
in  the  mouth  and  throat  followed  by  vomiting, 
purging,  collapse,  and  other  symptoms  of  toxic 
gastroenteritis.  Several  fatalities  have  been  re- 
ported. The  treatment  of  alum  poisoning  consists 
in  the  use  of  demulcent  drinks,  such  as  milk, 
combined  with  an  antacid  as  magnesia,  and  com- 
bating the  collapse  with  customary  stimulants. 


For  consideration  of  the  physiological  question 
of  the  effects  of  repeated  small  doses  of  alum,  see 
under  Aluminum. 

Dose,  as  an  astringent,  300  mg.  to  1  Gm.  (ap- 
proximately 5  to  15  grains);  as  an  emetic,  4  Gm. 
(approximately  1  drachm),  dissolved  in  water. 

Storage. — Preserve  "in  well-closed  contain- 
ers." N.F. 

Off.  Prep.— Exsiccated  Alum,  N.F. 

EXSICCATED  ALUM.     N.F. 

Dried  Alum,  Burnt  Alum,  Exsiccated  Ammonium  Alum, 
Exsiccated  Potassium  Alum,   [Alumen  Exsiccatum] 

"Exsiccated  Alum,  dried  at  200°  for  4  hours, 
contains  not  less  than  96.5  per  cent  of  AINH4- 
(S04)2  or  of  A1K(S04)2.  The  label  of  the 
container  must  indicate  whether  the  salt  is  Exsic- 
cated Ammonium  Alum  or  Exsiccated  Potassium 
Alum."  N.F. 

Alumen  Ustum.  Fr.  Alun  desseche.  Ger.  Gebrannter 
Alaun.  It.  Allume  usto;  allume  calcinato.  Sp.  Sulfato 
de  aluminio  y  de  potasio  anhidro;  Alumbre  Desecado; 
Alumbre  calcinado. 

Exsiccated  alum  may  be  prepared  by  heating 
alum,  at  a  temperature  of  about  200°,  until  the 
water  of  crystallization  has  been  volatilized. 

Description. — "Exsiccated  Alum  is  a  white, 
odorless  powder.  It  has  a  sweetish,  astringent 
taste,  and  absorbs  moisture  on  exposure  to  air. 
One  Gm.  of  Exsiccated  Alum  dissolves  very 
slowly  and  usually  incompletely  in  about  20  ml.  of 
water.  One  Gm.  of  it  dissolves  in  about  2  ml.  of 
boiling  water.  It  is  insoluble  in  alcohol."  N.F. 

Standards  and  Tests. — Identification. — Ex- 
siccated alum  responds  to  the  identification  tests 
under  alum.  Loss  on  drying. — Not  over  10  per 
cent,  on  drying  at  200°  for  4  hours.  Water- 
insoluble  substances. — Not  more  than  50  mg.  of 
residue  is  obtained  from  2  Gm.  of  exsiccated 
alum  added  to  40  ml.  of  water  and  occasionally 
agitated  during  24  hours,  the  insoluble  matter 
being  collected  on  counterbalanced  filter  papers 
or  in  a  tared  filtering  crucible  and  dried  at  105°. 
Alkalies  and  alkaline  earths. — Exsiccated  ammo- 
nium alum  meets  the  requirements  of  this  test 
under  alum,  allowance  being  made  for  the  differ- 
ence in  water  content.  Arsenic,  heavy  metals,  iron. 
— Exsiccated  alum  meets  the  requirements  of 
these  tests  under  alum,  allowance  being  made  for 
the  difference  in  water  content.  N.F. 

Assay. — A  sample  of  about  500  mg.  of  exsic- 
cated alum,  previously  dried  at  200°  for  4  hours, 
is  dissolved  in  water,  filtered  if  necessary,  and 
the  aluminum  precipitated  as  described  under 
Alum.  The  weight  of  the  aluminum  oxide  is  mul- 
tiplied by  4.652  to  obtain  the  equivalent  weight 
of  A1NH4(S04)2,  and  by  5.066  to  obtain  the 
weight  of  A1K(S04)2.  N.F. 

Uses. — Exsiccated  alum  has  the  same  me- 
dicinal properties  as  ordinary  alum,  but  it  is  much 
more  powerful  and  irritant  and  must  be  employed 
in  correspondingly  dilute  solutions.  It  has  mild 
escharotic  properties  and  is  occasionally  applied 
to  exuberant  granulations,  preferably  diluted  with 
inert  powders.  H 

Storage. — Preserve  "in  tight  containers."  N.F. 


54 


Aluminum 


Part   I 


ALUMINUM.    U.S.P. 

Al  (26.98) 


Ft.     Aluminium.     Gcr.     Aluminium. 
Aluminio. 


It.     Alluminio.     Sp. 


Next  to  oxygen  and  silicon,  aluminum  is  (he 
most  widely  distributed  and  abundant  element  on 
earth,  comprising  about  7.5  per  cent  of  the  earth's 
crust.  It  occurs  in  nature  only  in  combination. 
Feldspar,  mica,  zeolite,  hornblende,  leucite,  and 
shales  and  clays  are  silicates  of  aluminum;  corun- 
dum, emery,  and  such  gems  as  the  ruby  and  sap- 
phire are  naturally  occurring  oxides  of  aluminum. 
Many  other  gem  stones  contain  aluminum  in  one 
form  or  another.  Cryolite,  NaaAlFe,  and  bauxite, 
a  mixture  of  hydrated  aluminum  oxide  and  hy- 
drated  iron  oxide,  are  other  compounds  of  alumi- 
num found  in  nature;  bauxite  is  the  ore  commonly 
used  for  extraction  of  the  element. 

Sir  Humphry  Davy  in  1807  endeavored  to  ob- 
tain aluminum  by  electrolysis,  but  was  unsuc- 
cessful. It  was  obtained  by  Wohler  in  1827  by 
decomposition  of  anhydrous  aluminum  chloride 
with  potassium.  In  1854,  Deville  succeeded  in 
obtaining  the  pure  metal  in  ingots  by  decomposing 
aluminum  chloride  with  sodium.  The  process  of 
Deville  remained  the  only  practical  process  for 
its  manufacture  until  1886,  when  the  Messrs. 
Cowles  of  Cleveland,  Ohio,  succeeded  in  effecting 
the  reduction  of  corundum,  the  native  oxide,  by 
charcoal  with  the  aid  of  a  powerful  electric  cur- 
rent, using  large  carbon  electrodes.  This  process 
in  turn  has  been  practically  displaced  by  that  dis- 
covered by  Hall,  in  1886,  while  a  student  at  Ober- 
lin  College.  This  is  to  electrolyze  pure  alumina 
(aluminum  trioxide)  dissolved  in  a  bath  of  melted 
cryolite.  The  cryolite  is  continuously  regenerated, 
so  that  by  feeding  in  the  pure  alumina  the  process 
can  be  made  continuous. 

Description. — The  U.S.P.  describes  pow- 
dered aluminum  as  follows:  "Aluminum  is  a  very 
fine,  free-flowing,  silvery  powder,  free  from  gritty 
or  discolored  particles.  Aluminum  is  insoluble  in 
water  and  in  alcohol.  It  is  soluble  in  hydrochloric 
and  sulfuric  acids,  and  in  solutions  of  fixed  alkali 
hydroxides."  U.S.P.  The  whole  metal  has  a  silvery- 
white  appearance;  its  specific  gravity  is  about  2.7, 
its  melting  point  is  659°,  its  boiling  point  is  1800°. 
It  is  ductile,  soft,  and  moderately  resistant  to 
oxygen.  On  exposure  to  air,  the  metal  becomes 
coated  with  a  thin  layer  of  oxide,  which  serves  as 
a  protective  covering.  Aluminum  is  attacked 
slowly  by  organic  acids. 

It  has  found  wide  use  in  many  technical  fields 
due  primarily  to  its  light  weight  and  relative  sta- 
bility. The  strength  of  aluminum  is  greatly  in- 
creased by  alloying  with  copper  and  magnesium. 
Alloys  of  this  type  are  magnalium  and  duralumin. 
When  a  mixture  of  powdered  aluminum  and  iron 
oxide  is  ignited,  as  by  flaming  magnesium  ribbon, 
a  reaction  is  started  which  produces  a  temperature 
of  about  3000°,  the  iron  melting  and  being  used 
for  welding.  Thermite  is  such  a  mixture  which 
has  been  employed,  among  other  uses,  as  an  in- 
cendiary in  World  War  I. 

Standards  and  Tests. — Insoluble  matter. — 
Not  over  5  per  cent  is  insoluble  in  dilute  hydro- 


chloric acid  (1  in  2).  Alkalies  and  earths. — Not 
over  0.5  per  cent,  when  determined  by  precipi- 
tating the  aluminum  in  the  solution  obtained  in 
the  preceding  test  with  ammonia,  evaporating  the 
filtrate  to  dryness  and  igniting  the  residue. 
Arsenic. — The  limit  is  10  parts  per  million.  Heavy 
metals. — The  limit  is  20  parts  per  million.  Iron. — 
The  limit  is  0.5  per  cent.  Suitability. — Aluminum 
powder  is  smooth  and  unctous,  and  free  from 
gritty  particles,  when  rubbed  between  the  fingers. 
U.S.P. 

Physiological  Actions. — Aluminum  has  very 
feeble  physiologic  properties.  After  ingestion  very 
little  aluminum  is  absorbed  even  in  the  case  of 
soluble  salts.  McGuigan  (/.  Lab.  Clin.  Med.,  1927, 
12,  790)  finds  that  it  is  less  toxic  than  iron,  and 
Underhill  and  Peterman  (Am.  J.  Physiol.,  1929, 
90,  1)  reported  that  the  lethal  dose  of  aluminum 
chloride  for  various  animals  ranges  from  5  to  7 
Gm.  per  Kg.  after  subcutaneous  injection;  this 
would  correspond  to  a  dose  for  the  average  man 
of  about  8  pounds.  Small  traces  of  aluminum  are 
found  almost  always  in  the  tissues  and  blood 
of  man,  as  well  as  of  the  lower  animals.  (See 
Schwartze,  J.A.M.A.,  1933,  101,  1722).  From 
time  to  time  interested  persons  have  made  state- 
ments, usually  without  much  scientific  evidence, 
concerning  the  injurious  effects  of  small  quanti- 
ties of  aluminum  and  consequent  danger  from  the 
use  of  aluminum  cooking  utensils  or  alum  baking- 
powders.  The  U.  S.  Department  of  Agriculture  in 
1914  appointed  a  committee  under  the  chairman- 
ship of  Prof.  Ira  Remsen  to  investigate  whether 
the  use  of  aluminum  baking-powders  was  injuri- 
ous to  the  health.  As  a  result  of  the  study  of 
previous  researches,  as  well  as  experimental  work, 
they  concluded  that  aluminum,  in  the  quantities 
used  in  baking-powder,  had  no  injurious  effect 
upon  the  body.  Despite  the  assertions  of  Doellken 
(Arch.  exp.  Path.  Pharm.,  1897,  40)  that  the  re- 
peated injection  of  aluminum  causes  degenera- 
tion of  the  nerves,  and  the  findings  of  Seibert  and 
Wells  (Arch.  Path.,  1929,  8,  230)  that  such  in- 
jections caused  anemia,  the  whole  weight  of  our 
present  evidence  points  toward  the  innocuousness 
of  aluminum  kitchenware.  For  further  informa- 
tion on  this  subject,  see  J. A.M. A.,  1936,  106,  218; 
1951,  146,  477. 

Contact  dermatitis  in  aircraft  workers  due  to 
aluminum  or  its  alloys  has  been  reported.  Hall 
(J. A.M. A.,  1944,  125,  179)  saw  202  cases  of  con- 
tact dermatitis  among  755  employees  referred  to 
the  skin  clinic  during  6  months  from  plants  em- 
ploying over  6,000  persons.  Of  the  202  cases,  10 
were  due  to  Dural  (aluminum  95  per  cent,  copper 
3.5  per  cent,  manganese  and  magnesium  0.5  per 
cent  each,  and  traces  of  iron  and  silica)  ;  the  char- 
acteristics were :  scattered,  pale-pink,  fine  papules, 
which  were  usually  excoriated,  located  on  the 
forearms  in  all  cases  and  on  the  sides  of  the  neck 
in  half  the  cases;  the  etilogy  was  confirmed  by 
means  of  a  patch  test  with  the  metal  which  was 
not  read  until  48  to  72  hours  after  removal  of  the 
patch  to  avoid  the  immediate  irritant  effect  of  the 
metallic  particles.  Four  cases  were  due  to  alumi- 
num alone  and  were  distinctly  different — evanes- 
cent, wheal-like,  extremely  pruritic  lesions  de- 
veloped on  the  wrists  and  flexor  surface  of  the 


Part  I 


Aluminum  Acetate  Solution 


55 


forearms  during  each  work  period  and  usually 
cleared  up  over  week  ends. 

Like  others  of  the  so-called  heavy  metals,  alu- 
minum when  combined  in  an  easily  ionizable  salt, 
such  as  the  sulfate  or  chloride,  acts  as  an  astrin- 
gent. Its  insoluble  salts  are  used  both  as  protec- 
tives  and  adsorbents.  The  powdered  metal  or, 
more  conveniently,  an  aluminum  paste  (q.v.)  has 
been  employed  to  protect  the  skin  around  intes- 
tinal fistulae  from  the  digestive  action  of  the 
intestinal  contents.  It  is  for  this  use  that  the 
U.S. P.  recognizes  aluminum  powder.  A  prepara- 
tion containing  finely  powdered  metallic  aluminum 
mixed  with  glycerin  has  been  employed  as  a  sub- 
stitute for  the  insoluble  salts  of  bismuth  in  the 
treatment  of  gastric  ulcers  and  anal  fissures  (see 
Sussmann,  Ther.  Geg.,  May,  1908).  A  piece  of 
smooth,  polished  aluminum  has  been  employed  as 
a  dressing  for  indolent  wounds  with  success 
(Presse  med.,  1942,  50,  588).  Brown  (Am.  J. 
Surg.,  1948,  76,  594)  used  aluminum  foil  as  a 
dressing  for  burns.  Buettner  (J.A.M.A.,  1950, 
144,  737)  found  that  cloth  coated  with  aluminum 
foil  provided  the  best  protection  from  heat  for 
fire-fighting  equipment. 

Aluminum  in  the  form  of  the  powdered  metal 
or  the  amorphous  hydrated  alumina  is  employed 
in  the  treatment  of  silicosis  (pneumoconiosis). 
The  greatly  differing  incidence  of  silicosis  in  dif- 
ferent industries  suggested  the  presence  of  modi- 
fying factors  in  addition  to  the  number  and  size 
of  the  silica  particles  in  the  air.  Based  on  the 
observation  of  Denny  and  Robson  that  small 
amounts  of  aluminum  formed  a  coating  over  the 
silica  particles  which  almost  completely  inhibited 
the  solubility  of  silica  and  that  the  addition  of 
aluminum  powder  to  silica  would  prevent  the  de- 
velopment of  silicosis  in  animals,  Crombie,  Blais- 
dell  and  MacPherson  (Can.  Med.  Assoc.  J.,  1944, 
50,  318)  treated  44  employees  with  evidence  of 
silicosis  by  roentgen  examination  of  the  chest, 
some  of  whom  had  mild  symptoms  of  pulmonary 
fibrosis,  with  daily  inhalations  of  powdered  alu- 
minum produced  in  a  special  ball  mill.  Inhala- 
tions were  increased  from  5  minutes  to  30  minutes 
daily  and  continued  for  about  200  treatments. 
Symptomatic  improvement  was  observed  in  some 
of  the  men  and  none  of  them  showed  any  progres- 
sion of  their  silicosis  by  any  criteria  whereas  6  of 
9  control  cases  were  definitely  worse  at  the  end  of 
the  year.  Bamberger  (Ind.  Med.,  1945,  14,  477) 
and  MacGregar  (West  Virg.  M.  J.,  1945,  41,  229) 
confirm  these  observations.  Although  the  roentgen 
appearance  of  silicosis  has  been  reported  in  asso- 
ciation with  exposure  to  aluminum  dust  (Arch. 
Gewerbepath.  Gewerbehyg.,  1941,  11,  102,  cited 
in  J.A.M.A.,  1945,  127,  190),  this  has  not  been 
the  experience  of  Crombie  and  his  associates  nor 
of  others  (Gardner  et  al.,  J.  Indus t.  Hyg.  Toxicol., 
1944,  26,  211;  Hunter  et  al.,  Brit.  M.  J.,  1944,  1, 
159).  However,  bronchial  asthma  due  to  alumi- 
num in  an  employee,  who  also  showed  the  charac- 
teristic contact  dermatitis,  has  been  reported  by 
Cotter  (/.  Indust.  Hyg.  Toxicol.,  1943,  25,  421) 
and  by  others  previously.  The  therapeutic  or  pro- 
phylactic use  of  aluminum  powder  does  not  elimi- 
nate the  necessity  and  preferability  of  dust  con- 
trol in  industry  (Tabershaw,  New  Eng.  J.  Med., 


1945,  233,  437).  Furthermore,  Brown  and  Van 
Winkle  (J. A.M. A.,  1949,  140,  1024),  in  a  joint 
report  for  the  Councils  on  Industrial  Health  and 
Pharmacy  and  Chemistry  of  the  American  Medi- 
cal Association,  concluded  that  evidence  for  either 
the  safety  or  efficacy  of  prophylaxis  with  alumi- 
num was  not  available  and  was  not  likely  to  be- 
come available  because  of  the  nature  of  silicosis 
and  the  problems  of  industrial  exposure. 

Storage. — Preserve  "in  well-closed  contain- 
ers." U.S.P. 

ALUMINUM  ACETATE  SOLUTION. 

U.S.P. 

Burow's  Solution,  Liquor  Alumini  Acetatis 

"Aluminum  Acetate  Solution  yields  from  each 
100  ml.,  not  less  than  1.2  Gm.  and  not  more  than 
1.45  Gm.  of  AI2O3,  and  not  less  than  4.24  Gm. 
and  not  more  than  5.11  Gm.  of  acetic  acid 
(C2H4O2),  corresponding  to  not  less  than  4.8 
Gm.  and  not  more  than  5.8  Gm.  of  aluminum 
acetate  (CeHsAlOe)."  U.S.P. 

Add  15  ml.  of  glacial  acetic  acid  to  545  ml.  of 
aluminum  subacetate  solution  and  sufficient  water 
to  make  1000  ml.  Mix  and,  if  necessary,  filter. 
Up  to  0.6  per  cent  of  boric  acid  may  be  added  to 
stabilize  the  solution  (against  precipitation  of  a 
basic  compound).  Other  methods  of  producing 
the  aluminum  acetate,  as  by  reaction  between 
lead  acetate  and  aluminum  sulfate  (see  U.S.D., 
23rd  edition,  page  603,  for  formula),  may  be 
used  but  the  finished  product  must  meet  the 
U.S.P.  requirements.  Only  clear  aluminum  acetate 
solution  may  be  dispensed.  U.S.P. 

Description. — "Aluminum  Acetate  Solution  is 
a  clear,  colorless  liquid  having  a  faint  acetous 
odor,  and  a  sweetish,  astringent  taste.  Its  specific 
gravity  is  about  1.022."  U.S.P. 

Standards  and  Tests. — Identification. — Alu- 
minum acetate  solution  responds  to  tests  for  alu- 
minum and  for  acetate.  pH . — The  pH  of  the  solu- 
tion is  about  4.  Heavy  metals. — The  limit  is  10 
parts  per  million.  Limit  of  boric  acid. — After  neu- 
tralizing 25  ml.  of  aluminum  acetate  solution 
with  0.5  JV  sodium  hydroxide,  using  phenolph- 
thalein  T.S.  as  indicator,  glycerin  is  added  and 
the  resulting  strongly  ionized  complex  of  boric 
acid  is  titrated  with  0.5  N  sodium  hydroxide.  A 
blank  determination  is  performed  omitting  the 
aluminum  acetate  solution,  the  result  of  the  titra- 
tion of  which  is  subtracted  from  that  required 
for  the  solution  of  the  sample.  Each  ml.  of  the 
difference,  expressed  as  0.5  N  sodium  hydroxide, 
represents  30.92  mg.  of  boric  acid  (the  hydrogen 
equivalent  of  boric  acid  in  this  test  is  one). 
U.S.P. 

Assay. — For  aluminum  oxide. — From  a  sample 
of  10  ml.  of  aluminum  acetate  solution  the  alu- 
minum is  precipitated  as  hydroxide  by  ammonia 
T.S.  in  the  presence  of  ammonium  chloride.  The 
precipitate  is  collected  on  a  quantitative  filter, 
washed  with  hot  distilled  water,  dried  and  ignited 
to  AI2O3.  For  acetic  acid. — From  a  20-ml.  sample 
of  aluminum  acetate  solution  the  acetic  acid  is  dis- 
tilled into  a  measured  excess  of  0.5  N  sodium  hy- 
droxide and  the  excess  of  the  latter  determined  by 
titration  with  0.5  N  sulfuric  acid,  using  phenol- 


56 


Aluminum   Acetate   Solution 


Part   I 


phthalein  T.S.  as  indicator.  Each  cc.  of  0.5  N 
sodium  hydroxide  represents  30.03  mg.  of 
C2H4O2.  U.S.P. 

Uses. — Burow's  solution,  properly  diluted,  is 
very  useful  as  a  wet  dressing  in  the  treatment  of  a 
wide  range  of  dermatologic  conditions.  It  is  of  par- 
ticular value  in  treating  acute  vesicular  and 
weeping  dermatitis  of  the  eczematous,  contact 
type,  but  may  be  used  on  any  acute  or  subacute 
cutaneous  inflammation.  It  acts  by  a  combination 
of  detergent,  antiseptic,  astringent,  and  heat- 
dispersing  effects;  Combes  (N.Y.  State  J.  Med., 
1940,  40,  37)  stressed  the  importance  of  its 
buffering  action  in  maintaining  normal  skin  pH 
in  the  presence  of  inflammation.  Cooper  (Am.  J. 
Surg.,  1948,  75,  475)  found  the  solution  of  value 
as  cleansing,  adjuvant  therapy  in  stasis  dermatitis 
and  ulcers. 

Wet  dressings  of  aluminum  acetate  solution 
may  be  utilized  in  the  form  of  open  compresses 
applied  intermittently  to  affected  areas,  as  fixed 
closed  dressings  (the  solution  being  applied  to 
the  dressings),  or  as  soaks  in  acute  conditions  of 
the  hands  and  feet  (contact  eczema,  acute  der- 
matophytosis).  For  these  uses  the  official  alumi- 
num acetate  solution  should  be  diluted  with  20 
to  30  volumes  of  water.  A  combination  of  alumi- 
num sulfate  and  calcium  acetate,  known  as 
Domeboro  (Dome  Chemicals),  is  supplied  in  the 
form  of  effervescent  tablets  and  powders;  one 
tablet  or  powder  dissolved  in  a  pint  of  water 
provides  the  equivalent  of  a  1:20  solution  of 
aluminum  acetate. 

Burow's  solution  is  sometimes  incorporated 
in  dermatologic  lotions,  in  a  concentration  of 
about  10  per  cent;  it  is  also  an  ingredient  of 
the  "1-2-3"  paste  used  in  treating  acute  and 
chronic  eczematous  dermatoses  and  containing 
1  part  of  Burow's  solution,  2  parts  of  hydrophilic 
petrolatum  or  anhydrous  lanolin,  and  3  parts  of 
zinc  oxide  paste. 

Aluminum  acetate  solution  has  been  adminis- 
tered by  Ghormley  and  Hinchey  (/.  Bone  Joint 
Surg.,  1944,  26,  811)  to  patients  with  malacic 
diseases  of  bone.  The  treatment  was  based  on 
studies  by  Helfet.  who  used  feedings  of  aluminum 
acetate  to  diminish  phosphorus  intake  as  a  sub- 
stitute for  a  low  phosphorus  diet,  which  is  nearly 
impossible  to  achieve  when  a  high  calcium  intake 
is  desired.  Improvement  was  obtained  in  osteitis 
fibrosa,  osteoporosis.  Paget's  disease,  and  osteo- 
genesis imperfecta.  Their  patients  were  given 
Burow's  solution  in  a  vehicle  of  tolu  syrup  and 
honey;  adequate  supplies  of  milk  were  given 
daily.  H 

Aluminum  acetate  solution  is  applied  topically, 
commonly  being  diluted  with  10  to  40  volumes  of 
water. 

Storage. — Preserve  "in  tight  containers." 
U.S.P. 

ALUMINUM   CHLORIDE.     U.S.P. 

[Alumini  Chloridum] 

"Aluminum  Chloride,  when  dried  over  sulfuric 
acid  for  4  hours,  contains  not  less  than  95  per 
cent  of  AICI3.6H2O."  U.S.P. 

Aluminium  Chloride.  Aluminium  Chloratum.  Fr.  Chlorure 


d'aluminium.    Get.    Aluminiumchlorid.    It.    Cloruro    di    allu- 
minio.  Sp.  Cloruro  de  aluminio. 

Aluminum  chloride  may  be  prepared  by  heat- 
ing aluminum  in  chlorine,  or  by  reacting  alumi- 
num  hydroxide   with   hydrochloric   acid. 

Description. — "Aluminum  Chloride  is  a 
white  or  yellowish  white,  deliquescent,  crystalline 
powder.  It  is  nearly  odorless,  and  has  a  sweet, 
very  astringent  taste  and  its  solutions  are  acid  to 
litmus  paper.  One  Gm.  of  Aluminum  Chloride 
dissolves  in  about  0.9  ml.  of  water  and  in  about 
4  ml.  of  alcohol.  It  is  soluble  in  glycerin."  U.S.P. 

Standards  and  Tests. — Identification. — A  1 
in  10  solution  of  aluminum  chloride  responds  to 
tests  for  aluminum  and  for  chloride.  Sulfate. — 
No  turbidity  is  produced  in  1  minute  after  adding 
0.2  ml.  of  barium  chloride  T.S.  to  10  ml.  of  a  1 
in  100  solution  of  aluminum  chloride.  Alkalies 
and  alkaline  earths. — Not  more  than  0.5  per  cent 
of  residue  is  obtained  on  evaporating  the  filtrate 
from  a  solution  of  aluminum  chloride  from  which 
the  aluminum  has  been  precipitated  by  ammonia 
T.S.  Arsenic. — Aluminum  chloride  meets  the  re- 
quirements of  the  test  for  arsenic.  Heavy  metals. 
— The  limit  is  20  parts  per  million.  Iron. — The 
limit  is  10  parts  per  million.  U.S.P. 

Assay. — A  sample  of  about  500  mg.  of  alumi- 
num chloride,  previously  dried  for  4  hours  over 
sulfuric  acid,  is  dissolved  in  water  and  the  alumi- 
num precipitated  as  explained  under  Alum.  Each 
Gm.  of  aluminum  oxide  represents  4.736  Gm.  of 
AICI3.6H2O.  U.S.P. 

Uses. — Aluminum  chloride  is  employed  exter- 
nally as  an  astringent  and  antiseptic,  especially  in 
hyperhidrosis.  It  is  commonly  used  as  a  25  per 
cent  solution,  applied  lightly  and  only  to  un- 
broken skin;  solutions  as  dilute  as  10  per  cent 
are  sometimes  used.  If  irritation  occurs  the 
solution  should  be  washed  off.  Aluminum  chloride 
is  an  ingredient  in  many  proprietary  preparations 
for  diminishing  local  sweating.  The  salt  is  no 
longer  used  internally. 

Storage. — Preserve  "in  tight  containers." 
U.S.P. 

ALUMINUM  HYDROXIDE  GEL.    U.S.P. 

Colloidal  Aluminum  Hydroxide,  Gelatum 
Alumini  Hydroxidum 

"Aluminum  Hydroxide  Gel  is  a  suspension  con- 
taining the  equivalent  of  not  less  than  3.6  per 
cent  and  not  more  than  4.4  per  cent  of  aluminum 
oxide  (AI2O3),  in  the  form  of  aluminum  hydroxide 
and  hydrated  oxide.  It  may  contain  peppermint 
oil,  glycerin,  sorbitol,  sucrose,  saccharin,  or  other 
suitable  agents  for  flavoring  purposes,  and  it  may 
contain  sodium  benzoate,  benzoic  acid,  or  other 
suitable  agents,  in  a  total  amount  not  exceeding 
0.5  per  cent,  as  a  preservative."  U.S.P. 

Sp.  Hidrato  de  Aluminio  Gelatinado. 

The  U.S.P.  LX  recognized  under  the  title  Alu- 
mini Hydroxidum  the  precipitate  formed  by  mix- 
ing solutions  of  sodium  carbonate  and  of  alum. 
This  was  a  white,  bulky,  amorphous  powder, 
relatively  inefficient  as  a  gastric  antacid.  It  was 
used  as  a  protective  and  mild  astringent  in  the 
treatment  of  irritated  conditions  of  the  skin  in 
much  the  same  way  as  zinc  oxide  is  employed. 


Part  I 


Aluminum   Hydroxide   Gel  57 


Aluminum  hydroxide  gel  may  be  prepared  by  a 
number  of  methods;  the  products  vary  widely  in 
viscosity  and  particle  size,  and  hence  in  the  rate 
of  solution  in  acids.  It  is  known  that  such  factors 
as  the  degree  of  supersaturation  with  respect  to 
aluminum  hydroxide,  the  pH  during  precipitation, 
the  temperature,  and  the  nature  and  concentration 
of  by-product  ions  present  are  important  in  deter- 
mining the  physical  and,  to  an  extent,  the  chemical 
properties  of  the  aluminum  hydroxide. 

While  details  of  the  manufacturing  processes 
are  not  disclosed  one  manufacturer  of  an  elegant 
preparation  reacts  aluminum  chloride  with  a  solu- 
tion containing  sodium  carbonate  and  sodium 
bicarbonate,  the  product  of  this  reaction  is  re- 
ported to  be  mixed  with  the  precipitate  obtained 
by  reacting  solutions  of  aluminum  chloride  and  of 
ammonia.  The  mixed  magma  is  dialyzed  in  canvas 
bags,  the  product  is  mixed  with  some  glycerin,  so- 
dium benzoate  is  added,  and  the  mixture  passed 
through  a  colloid  mill. 

This  product  is  available  under  its  official  name 
and  under  several  trade  names  including:  Ampho- 
jel  (Wyeth),  Creamalin  (Winthrop-Stearns),  and 
Vanogel  (Vanpelt  &  Brown).  Hydrogel  (Breon) 
contains  more  aluminum  hydroxide  than  does  the 
official  product  and  Flaagel  (Breon)  differs  in 
that  it  contains  color  and  orange  flavor. 

Description. — "Aluminum  Hydroxide  Gel  is 
a  white,  viscous  suspension,  from  which  small 
amounts  of  clear  liquid  may  separate  on  stand- 
ing." U.S.P. 

Standards  and  Tests. — Identification. — A  so- 
lution of  aluminum  hydroxide  gel  in  hydrochloric 
acid  responds  to  tests  for  aluminum.  Reaction. — 
Both  red  and  blue  litmus  paper  are  slightly  af- 
fected by  aluminum  hydroxide  gel,  but  phenol- 
phthalein  T.S.  is  not  reddened.  Acid-consuming 
capacity. — About  1.5  ml.  of  the  gel,  accurately 
weighed,  is  reacted  with  SO  ml.  of  0.1  N  hydro- 
chloric acid,  at  37.5°  for  1  hour;  the  excess  acid 
is  titrated  with  0.1  N  sodium  hydroxide,  using 
bromophenol  blue  T.S.  as  indicator.  Each  Gm. 
of  gel  requires  not  less  than  12.5  ml.  and  not 
more  than  25  ml.  of  0.1  N  acid.  Chloride. — The 
limit  is  0.28  per  cent.  Sulfate. — The  limit  is  500 
parts  per  million.  Arsenic. — The  limit  is  0.8  part 
per  million.  Heavy  metals. — The  limit  is  5  parts 
per  million.  U.S.P. 

Assay. — About  5  Gm.  of  gel,  accurately 
weighed,  is  dissolved  in  a  solution  of  hydrochloric 
acid  and  the  aluminum  ion  precipitated  as  hy- 
droxide by  ammonia  T.S.  The  precipitate  is  ig- 
nited to  constant  weight  as  AI2O3.  U.S.P. 

Uses. — Colloidal  aluminum  hydroxide  is  used 
almost  exclusively  as  a  gastric  antacid,  especially 
in  the  treatment  of  peptic  ulcer.  In  the  stomach 
it  neutralizes  hydrochloric  acid,  forming  aluminum 
chloride  and  water.  Schiffrin  and  Komarov  (Am. 
J.  Digest.  Dis.,  1941,  8,  215)  reported  that  the 
aluminum  ion  inhibits  pepsin  activity  even  in  acid 
solution.  No  more  hydroxyl  ions  are  liberated 
than  are  necessary  for  neutralization  of  the  acid. 
Each  Gm.  of  the  official  suspension  will  neutralize 
to  pH  3.5  from  12.5  to  25  ml.  of  gastric  juice 
having  an  acidity  corresponding  to  0.1  N  hydro- 
chloric acid.  The  rate  of  this  neutralization  is 
comparable    to   that   of   milk   or   egg,    requiring 


from  5  to  15  minutes.  It  acts  more  slowly  than 
the  soluble  alkalies,  such  as  sodium  bicarbonate 
which  rapidly  neutralizes  acid  to  pH  7  or  higher 
(Adams,  Arch.  Int.  Med.,  1939,  63,  1030).  In 
a  study  of  gastric  antacids  to  determine  the  rate 
and  extent  of  neutralization  of  0.1  N  hydro- 
chloric acid,  added  at  30  minute  intervals  to 
simulate  continuous  gastric  secretion,  Hammar- 
lund  and  Rising  (J.A.Ph.A.,  1949,  38,  586) 
found  that  aluminum  hydroxide  gradually  raises 
the  pH  to  about  4,  maintains  this  value  for  2 
or  3  hours,  and  then  gradually  loses  its  antacid 
effect,  while  magnesium  trisilicate  rather  more 
quickly  raises  the  pH  to  5  or  6  but  main- 
tains this  for  only  a  short  time  before  its  antacid 
effect  is  almost  completely  and  abruptly  spent. 
In  the  alkaline  portion  of  the  intestine  the  alumi- 
num chloride  reacts  to  produce  insoluble  alu- 
minum compounds  while  releasing  an  equivalent 
amount  of  chloride  which  is  restored  to  the 
system. 

Aluminum  hydroxide  possesses  adsorbent  prop- 
erties toward  many  substances.  Because  of  its 
lack  of  alkaline  character  it  does  not  produce  a 
rebound  secretion  of  hydrochloric  acid  in  the 
stomach,  as  is  the  case  with  the  soluble  alkalies. 
Because  of  its  insolubility  it  is  practically  unab- 
sorbable  from  the  alimentary  tract  and  hence 
there  is  no  danger  of  disturbing  the  pH  balance  of 
the  system,  of  impairing  renal  function,  or  of 
having  toxic  effects  (Kirsner,  Am.  J.  Digest.  Dis., 
1941,  8,  160).  It  interferes,  however,  with  the 
absorption  of  phosphates  from  the  intestine  and  in 
the  presence  of  a  low  phosphorus  diet  may  cause 
a  deficiency  (Fauley  et  al.,  Arch.  Int.  Med., 
1941,  67,  563).  It  is  prescribed  for  this  purpose 
in  the  treatment  of  renal  rickets,  chronic  uremia 
and  phosphatic  renal  calculi  (Shorr  and  Carter, 
1950,  144,  1549).  Page  and  Page  (Obstet.  Gynec, 
1953,  1,  94)  relieved  the  muscular  leg  cramps 
which  occurred  in  about  half  of  their  well-fed 
pregnant  patients  by  prescribing  0.6  Gm.  of  alu- 
minum hydroxide  three  times  daily  or  by  re- 
ducing the  consumption  of  milk,  which  provides 
an  excess  of  phosphorus  in  relation  to  calcium. 
It  appears  not  to  interfere  with  absorption  of 
amino  acids,  ascorbic  acid,  glucose,  and  neutral 
fat  (Hoffman  and  Dyniewicz,  Gastroenterology , 
1946,  6,  50).  Some  clinicians  have  claimed  excel- 
lent results  in  various  forms  of  enteritis  due  to 
its  adsorbent  oower.  Eyerly  and  Breuhaus 
(J.A.M.A.,  1937,  109,  191)  reported  favorably 
on  the  use  of  enemas  of  aluminum  hydroxide  gel 
and  kaolin  in  ulcerative   colitis. 

The  most  important  medicinal  use  of  aluminum 
hydroxide  is  in  the  treatment  of  peptic  ulcer,  in 
which  the  persistence  of  its  antacid  effect  is  of 
especial  importance,  but  it  appears  also  to  act  as 
a  protecitve  in  these  cases  and  to  exercise  some 
other  beneficial,  perhaps  astringent,  action  beyond 
that  of  merely  correcting  the  acidity;  it  is  prob- 
able that  it  has  a  protective  action  on  the  raw 
surface.  For  literature  on  the  use  of  this  drug  see 
the  report  of  the  Council  on  Pharmacy,  J.A.M.A., 
1941,  117,  1356.  Collins  (J.A.M.A.,  1945,  127, 
899)  has  reported  the  satisfactory  use  of  alumi- 
num hydroxide  gel  in  the  management  of  3,000 
patients  with  peptic  ulcer  over  a  period  of  many 


58 


Aluminum   Hydroxide   Gel 


Part  I 


years  (see  also  Rossett  et  al,  Ann.  Int.  Med., 
1952,  36,  98).  The  more  prolonged  and  effective 
action  of  aluminum  hydroxide  enabled  the  ma- 
jority of  patients  to  follow  a  regimen  compatible 
with  their  occupations,  although  general  hygienic 
measures,  diet  and  alleviation  of  mental  tension 
could  not  be  neglected.  Its  constipating  action 
in  some  cases  is  undesirable;  the  simultaneous 
use  of  laxatives  may  be  required.  The  tendency 
of  the  peptic  ulcer  patient  to  constipation  is  fa- 
vored by  the  low-residue,  bland  diet  usually 
prescribed.  Batterman  and  Ehrenfeld  {Gastroen- 
terology, 1947,  9,  141)  reported  the  incidence 
of  constipation  with  various  antacids  as  follows: 
non-reactive  aluminum  hydroxide  gels,  30  to  35 
per  cent;  reactive  aluminum  hydroxide  gels,  16 
to  33  per  cent;  magnesium  trisilicate.  14  to  15 
per  cent.  Kirsner  et  al.  (Ann.  Int.  Med.,  1951, 
35,  7S5)  pointed  out  that  no  antacid  in  a  single 
dose  was  capable  of  neutralizing  the  night-time 
hypersecretion  of  the  duodenal  ulcer  patient. 
For  cases  refractory-  to  usual  medical  man- 
agement Winkelstein  and  Hollander  (Surgery, 
1945,  17,  696)  and  others  employed  with  success 
a  continuous  intragastric  drip  of  aluminum  hy- 
droxide gel  or  a  mixture  of  milk  and  sodium 
bicarbonate.  Woldman  (Am.  J.  Digest.  Dis., 
1941,  8,  39)  reported  that  the  continuous  method 
of  administration  was  particularly  beneficial  in 
bleeding  peptic  ulcer.  In  their  most  successful 
management  of  the  bleeding  peptic  ulcer  patient, 
Dunphy  and  Gray  (Mod.  Med.,  March  1,  1952, 
p.  90)  employed  hourly  feedings  of  100  ml.  of 
warm  milk  and  cream  with  10  ml.  of  aluminum 
hydroxide  gel  every  hour  during  the  day  and 
double  these  quantities  even-  2  hours  during 
the  night  along  with  phenobarbital,  atropine, 
vitamins,  and  blood  replacement,  with  operation 
if  shock  was  not  corrected  by  transfusions.  Binder 
and  Paul  (Am.  J.  Digest.  Dis.,  1952,  19,  278) 
reported  good  results  in  the  bleeding  case  with  a 
similar  medical  management.  Cantor  et  al.  (Am. 
J.  Surg.,  1950.  80,  SS3)  gave  gelfoam  and  throm- 
bin by  mouth  to  form  a  clot  in  such  cases  and 
used  aluminum  hydroxide  gel  to  prevent  diges- 
tion of  the  thrombin  and  the  clot. 

Howard  (U.  S.  Nov.  M.  Bull,  1945,  44,  1047) 
reported  prompt  relief  and  rapid  healing  from 
local  application  of  aluminum  hydroxide  gel  to 
a  variety  of  skin  conditions,  such  as  miliaria 
rubra,  tinea  cruris  or  circinata,  weeping  eczema- 
tous  lesions,  impetigo  and  epidermophytosis. 
Friedman  et  al.  (Am.  J.  Digest.  Dis.,  1948,  15, 
57)  effectively  employed  a  paste  in  moist,  but 
not  in  dry.  types  of  pruritus  ani. 

Aluminum  hydroxide  gel  has  been  used  as  a 
vehicle  to  increase  the  absorption  of  orally  ad- 
ministered penicillin  (J. A.M. A.,  1945,  128,' 845; 
1945,  129,  315).  Administration  of  aluminum 
hydroxide  with  anticholinergic  drugs,  such  as  atro- 
pine sulfate,  given  by  mouth  to  animals,  was 
found  by  Seifter  et  al.  (I.  Pharmacol.,  1952,  105, 
96)  to  retard  the  absorption  of  the  latter  but  to 
prolong  its  action  considerably.  Clinical  studies 
by  Berkowitz  (Antibiot.  Chemother.,  1953.  3, 
618)  demonstrated  that  the  addition  of  aluminum 
hydroxide  gel  to  a  triple  sulfonamide  mixture 
increased   and   prolonged    the    concentration   of 


sulfonamide  in  the  blood.  Simultaneous  adminis- 
tration of  aluminum  hydroxide  with  aminophyl- 
line  decreased  the  incidence  of  gastrointestinal 
disturbances  to  such  a  degree  that  sufficient  of 
the  latter  compound  could  be  given  orally  to  at- 
tain levels  of  theophylline  in  the  blood  which 
are  comparable  to  those  obtained  by  intravenous 
administration  of  aminophylline  (Cronheim  et  al., 
Postgrad.  Med.,  1953,  13,  432);  the  aluminum 
hydroxide  appears  not  to  alter  the  rate  or  the 
degree  of  absorption  of  the  aminophylline.  With 
chlortetracycline  (Aureomycin  > ,  aluminum  hy- 
droxide gel  relieves  the  frequent  gastrointestinal 
disturbances  but  it  also  decreases  the  blood  con- 
centration of  the  antibiotic  (Waisbren  and  others, 
J.A.M.A.,  1949,  141,  938;  Boger  et  al,  J.  Phila. 
Gen.  Hosp.,  1950,  1,  3)  and  changes  its  effect 
on  fecal  urobilinogen  and  fecal  bacterial  flora 
(Hayford  and  Waisbren.  Surgery,  1952, 31, 361).  S 

Dose. — The  usual  dose  of  aluminum  hydroxide 
gel  is  8  ml.  (2  fluidrachms),  with  half  a  glass  of 
water,  3  to  6  times  daily,  about  one  hour  after 
meals  and  at  bedtime.  It  may  be  taken  as  fre- 
quently as  every  two  hours.  The  range  of  dose  is 
4  to  30  ml.;  generally  not  over  60  ml.  is  to  be 
taken  in  24  hours. 

Storage. — Preserve  '"in  tight  containers  and 
avoid  freezing/'  U.S.P. 

DRIED  ALUMINUM  HYDROXIDE 
GEL.    U.S.P. 

Gelatum  Alumini  Hydroxidi  Siccum 

''Dried  Aluminum  Hydroxide  Gel  yields  not 
less  than  50  per  cent  of  aluminum  oxide  (AI2O3)." 
U.S.P. 

Sp.  Hidrato  de  Aluminio  Gclatinado  Seco. 

Dried  aluminum  hydroxide  gel  is  prepared  by 
drying,  at  not  too  high  temperature,  the  magma 
of  aluminum  hydroxide  obtained  in  preparing 
the  liquid  gel  (see  preceding  monograph)  prior 
to  addition  of  glycerin  or  preservative.  Products 
on  the  market  differ  widely  in  bulk  and  rate  of 
solution  because  of  variation  in  the  temperature 
and  rate  of  drying,  as  well  as  variation  in  the 
factors  discussed  under  Aluminum  Hydroxide  Gel. 

Description. — "Dried  Aluminum  Hydroxide 
Gel  is  a  white,  odorless,  tasteless,  amorphous 
powder.  Dried  Aluminum  Hydroxide  Gel  is  in- 
soluble in  water  and  in  alcohol.  It  is  soluble  in 
diluted  mineral  acids  and  in  solutions  of  fixed 
alkali  hydroxides.''  U.S.P. 

Standards  and  Tests. — Identification. — A  so- 
lution of  500  mg.  of  dried  aluminum  hydroxide 
gel  in  10  ml.  of  diluted  hydrochloric  acid  responds 
to  tests  for  aluminum.  Reaction. — The  filtrate 
from  a  suspension  of  1  Gm.  of  dried  gel  in  25  ml. 
of  water  is  neutral  to  litmus  paper.  Acid-con- 
suming capacity. — Each  Gm.  of  dried  aluminum 
hydroxide  gel  requires  not  less  than  250  ml.  of 
0.1  N  hydrochloric  acid  (see  this  test  under 
Aluminum  Hydroxide  Gel).  Chloride. — The  limit 
is  0.84  per  cent.  Sulfate. — The  limit  is  0.6  per 
cent.  Arsenic  and  heavy  metals. — Dried  aluminum 
hydroxide  gel  meets  the  requirements  of  the  cor- 
responding tests  under  Aluminum  Hydroxide  Gel, 
allowance  being  made  for  the  difference  in  content 
of  AI2O3.  U.S.P. 


Part  I 


Aluminum   Phosphate  Gel  59 


Assay. — A  sample  of  about  400  mg.  of  dried 
gel  is  assayed  in  a  manner  similar  to  that  sum- 
marized under  the  assay  for  Aluminum  Hydroxide 
Gel.  U.S.P. 

Uses. — In  the  form  of  tablets  this  is  a  con- 
venient method  of  administering  aluminum  hy- 
droxide gel.  The  following  are  proprietary  names 
for  the  tablets:  Alugel  (Cole),  Amphojel 
(Wyeth),  Creamalin  (Winthrop),  Drydgel  (Fair- 
child),  and  Vanogel  (Vanpelt  &  Brown).  For  an 
account  of  its  therapeutic  uses  see  under  Alumi- 
num Hydroxide  Gel.  The  antacid  action  of  the 
dry  form  is  less  rapid  and  efficient  than  that  of 
the  gel.  Tablets  should  probably  be  chewed  for 
best  results. 

The  usual  dose  is  300  mg.  (approximately  5 
grains)  4  times  daily;  the  range  of  dose  is  300  mg. 
to  2.4  Gm. 

Storage. — Preserve  "in  tight  containers." 
U.S.P. 

ALUMINUM  PASTE.  U.S.P. 

"Aluminum  Paste  contains  not  less  than  9  per 
cent  and  not  more  than  10  per  cent  of  Al."  U.S.P. 

Levigate  100  Gm.  of  aluminum,  in  very  fine 
powder,  with  50  Gm.  of  liquid  petrolatum  to  a 
smooth  paste  and  then  incorporate  this  mixture 
with  850  Gm.  of  zinc  oxide  ointment.  U.S.P. 

Assay. — A  1-Gm.  portion  of  aluminum  paste 
is  heated  with  a  mixture  of  sulfuric  and  nitric 
acids  to  oxidize  as  much  of  the  fatty  base  as  pos- 
sible, while  also  dissolving  the  aluminum.  The  pH 
of  the  liquid  is  adjusted  to  2.5  and  the  zinc  is 
precipitated  as  sulfide.  Aluminum  in  the  filtrate 
is  precipitated  as  hydrous  aluminum  oxide  by  add- 
ing ammonium  hydroxide,  and  the  precipitate  is 
finally  weighed  as  AI2O3.  The  weight  of  Al  in  the 
sample  is  calculated  by  multiplying  the  weight 
of  the  oxide  by  0.5292.  U.S.P. 

Use. — As  mentioned  in  the  article  on  alumi- 
num, this  paste  is  a  convenient  means  of  applying 
the  powdered  metal  around  intestinal  fistulae  to 
protect  the  surrounding  skin  against  the  digestive 
action  of  the  intestinal  contents. 

Storage. — Preserve  "in  well-closed  containers, 
and  avoid  prolonged  exposure  to  temperatures 
above  30°."  U.S.P. 

ALUMINUM  PHOSPHATE  GEL.    U.S.P. 

[Gelatum  Alumini  Phosphatis] 

"Aluminum  Phosphate  Gel  is  a  water  suspen- 
sion containing  not  less  than  3.8  per  cent  and  not 
more  than  4.5  per  cent  of  aluminum  phosphate 
(AIPO4).  It  may  contain  peppermint  oil,  glycerin, 
sorbitol,  sucrose,  saccharin,  or  other  suitable 
agents  for  flavoring  purposes,  and  it  may  contain 
sodium  benzoate,  benzoic  acid,  or  other  suitable 
agents,  in  an  amount  not  exceeding  0.5  per  cent, 
as  a  preservative."  U.S.P. 

Phosphaljel  (Wyeth).  Sp.  Gel  de  Fosfato  de  Aluminio. 

Aluminum  phosphate  gel  may  be  prepared  by 
the  interaction  of  an  aluminum  salt  with  a  phos- 
phate; the  product,  like  aluminum  hydroxide  gel, 
varies  in  viscosity  and  particle  size  depending  on 
the  pH  of  the  reaction  mixture,  the  temperature, 
and  the  concentration  and  the   particular  salts 


used  as  the  source  of  the  interacting  ions.  After 
precipitation  of  the  aluminum  phosphate  the 
product  is  dialyzed,  mixed  with  one  or  more  of 
the  substances  officially  permitted  to  be  used  for 
stabilizing,  preserving  and  flavoring  purposes, 
and  passed  through  a   colloid  mill. 

Description. — "Aluminum  Phosphate  Gel  is 
a  white,  viscous  suspension  from  which  small 
amounts  of  water  may  separate  on  standing." 
U.S.P. 

Standards  and  Tests. — Identification. — (1) 
A  solution  of  the  gel  in  hydrochloric  acid  responds 
to  tests  for  Aluminum.  (2)  A  solution  of  the  gel 
in  diluted  nitric  acid  responds  to  tests  for  phos- 
phate. pH — The  pH  of  the  gel,  at  25°,  is  be- 
tween 6.0  and  7.2.  Reaction  rate. — A  mixture  of 
30  ml.  of  0.1  N  hydrochloric  acid  and  6  Gm.  of 
gel,  heated  at  37°  for  15  minutes,  has  a  pH  be- 
tween 2.0  and  2.5.  Chloride. — Not  over  0.16 
per  cent.  Soluble  phosphate. — Not  over  700  parts 
per  million,  calculated  as  PO-i.  Sulfate. — Not 
over  500  parts  per  million.  Arsenic. — Not  over 
0.8  part  per  million.  Heavy  metals. — The  limit  is 
5  parts  per  million.  Acid-consuming  capacity. — 
About  250  mg.  of  the  gel,  accurately  weighed,  is 
digested  with  30  ml.  of  0.1  N  hydrochloric  acid 
at  37°  for  30  minutes;  the  excess  acid  is  titrated 
with  0.1  A7  sodium  hydroxide,  using  thymol  blue 
T.S.  and  titrating  to  a  pH  of  2.5.  Each  Gm.  of  gel 
requires  not  less  than  5  and  not  more  than  9  ml. 
of  0.1  A7  acid.  U.S.P. 

Assay. — A  20  Gm.  portion  of  gel  is  dissolved 
in  nitric  acid  and  diluted  to  100  ml.  with  distilled 
water.  From  a  10-ml.  portion  of  this  solution  the 
phosphate  is  precipitated  as  ammonium  phos- 
phomolybdate  with  ammonium  molybdate  T.S. 
The  precipitate  is  filtered,  washed  first  with  a 
nitric  acid  solution,  then  with  1  per  cent  potas- 
sium nitrate  and  dissolved  in  50  ml.  of  0.5  N 
sodium  hydroxide;  the  excess  of  alkali  is  titrated 
with  0.5  N  sulfuric  acid,  using  phenolphthalein 
T.S.  as  indicator.  The  reaction  of  ammonium 
phosphomolybdate  and  sodium  hydroxide  may 
be  represented  by  the  following  equation: 

(NH.4)3P04.12Mo03  +  23NaOH  -* 

llNa2Mo04  +  (NH.4)2Mo04  + 

NaNH.4HP04+  IIH2O 

from  which  it  is  apparent  that  the  equivalent 
weight  of  AIPO4  is  ^3  of  its  molecular  weight, 
one  molecule  of  ammonium  phosphomolybdate 
being  precipitated  for  each  molecule  of  aluminum 
phosphate  undergoing  reaction.  Each  ml.  of 
0.5  N  sodium  hydroxide  represents  2.651  mg.  of 
AIPO4.  U.S.P. 

Uses. — Aluminum  phosphate  gel  is  employed 
in  the  treatment  of  peptic  ulcer  and  is  particu- 
larly advocated  for  the  patient  with  postoperative, 
jejunal  (marginal)  ulcer  (Fauley  et.  al.,  Arch. 
Int.  Med.,  1941,  67,  563;  Collins,  J. A.M. A., 
1945,  127,  899).  Whereas  aluminum  hydroxide 
failed  to  prevent  the  development  of  postoperative 
jejunal  ulcer  in  Mann-Williamson  dogs  in  which 
there  is  a  relative  deficiency  of  bile  and  pancreatic 
juice,  aluminum  phosphate  gel  was  shown  to  be 
effective  both  as  a  preventive  and  a  therapeutic 
agent  in  such  dogs.  Clinical  experience  has  con- 
firmed  the  superiority   of   aluminum  phosphate 


60 


Aluminum    Phosphate   Gel 


Part   I 


over  aluminum  hydroxide  in  the  management  of 
peptic  ulcer  in  patients  who  have  a  deficiency  of 
pancreatic  juice,  a  chronic  diarrhea  or  a  dietary 
deficiency  in  phosphorus.  Lichstein  et  al.  (Am.  J. 
Digest.  Dis.,  1945,  12,  65)  reported  good  results 
in  patients  with  uncomplicated  peptic  ulcer  and 
bleeding  peptic  ulcer. 

The  range  of  dose  is  15  to  30  ml.  (approxi- 
mately 4  to  8  fluidrachms),  alone  or  with  a  little 
water,  as  frequently  as  even'  2  hours  if  necessary. 
The  total  dose  in  24  hours  usually  does  not 
exceed  100  ml. 

Storage. — Preserve  ''in  tight  containers." 
U.S.P. 


ALUMINUM  SUBACETATE  SOLU- 
TION. U.S.P. 

Liquor  Alumini  Subacetatis 

"Aluminum  Subacetate  Solution  yields,  from 
each  100  ml.,  not /less  than  2.30  Gm.  and  not 
more  than  2.60  Gm.  of  aluminum  oxide  (AI2O3), 
and  not  less  than  5.43  Gm.  and  not  more  than 
6.13  Gm.  of  acetic  acid  (C2H4O2)."  U.S.P. 

Liquor  Aluminii  Acetici  (Ger.,  It.).  Fr.  Solution  d'acetate 
d'aluniinium.  Ger.  Aluminiumazetatlbsung.  It.  Acetato  di 
alluminio  liquido. 

Dissolve  160  Gm.  of  aluminum  sulfate  in  600 
ml.  of  water,  filter  the  solution,  and  gradually  add 
70  Gm.  of  precipitated  calcium  carbonate,  in  sev- 
eral portions,  with  constant  stirring.  Now  slowly 
add  160  ml.  of  acetic  acid,  mix,  and  set  the  mix- 
ture aside  for  24  hours.  Filter  the  mixture  through 
a  Buchner  funnel,  wash  the  magma  on  the  filter 
with  small  portions  of  cold  water  until  the  filtrate 
measures  1000  ml.  The  solution  may  be  stabilized 
(against  precipitation)  by  the  addition  of  not 
more  than  0.9  per  cent  of  boric  acid.  Other 
methods  of  producing  the  aluminum  subacetate 
may  be  used  but  the  finished  product  must  meet 
the  U.S.P.  requirements.  U.S.P. 

Description. — ''Aluminum  Subacetate  Solu- 
tion is  a  clear,  colorless,  or  faintly  yellow  liquid, 
having  an  acetous  odor  and  an  acid  reaction  to 
litmus.  It  gradually  becomes  turbid  on  continued 
standing,  due  to  separation  of  a  more  basic  salt." 
U.S.P. 

Standards  and  Tests. — Identification. — 
Aluminum  subacetate  solution  responds  to  tests 
for  aluminum  and  for  acetate.  Limit  for  boric 
acid. — This  test  is  performed  as  directed  under 
Aluminum  Acetate  Solution.  U.S.P. 

Assay. — The  assay  for  aluminum  oxide  and 
that  for  acetic  acid  are  performed  as  directed 
under  Aluminum  Acetate  Solution.  U.S.P. 

Uses. — Aluminum  subacetate  solution  is  use- 
ful as  an  astringent  and  antiseptic  wash.  Diluted 
with  20  to  40  volumes  of  water  it  is  employed  as 
a  wet  dressing  in  acute,  vesicular  and  exudative 
eczematous  conditions  of  the  skin;  occasionally 
somewhat  stronger  solutions  are  applied.  It  was 
formerly  used  as  a  gargle  for  local  treatment  of 
inflamed  conditions  of  the  throat. 

Storage. — Preserve  "in  tight  containers." 
US.P. 

Off.  Prep. — Aluminum  Acetate  Solution, 
US.P. 


ALUMINUM   SULFATE.     U.S.P. 

[Alumini  Sulfas] 

"Aluminum  Sulfate  contains  an  amount  of 
Ab(S04)3  equivalent  to  not  less  than  99.5  per 
cent  and  not  more  than  112  per  cent  of 
Al2(S04)3.18HoO."  US.P. 

Aluminium  Sulfate;  Concentrated  Alum;  Pearl  or  Pickle 
Alum.  Aluminium  Sulfuricum;  Sulfas  Aluminicus;  Alum- 
inii Sulphas.  Fr.  Sulfate  d'aluminium;  Sulfate  d'alumine 
pur.  Ger.  Aluminiumsulfat ;  Schwefelsaures  Aluminium; 
Schwefelsaure  Tonerde.  It.  Solfato  di  alluminio.  Up. 
Sulfato  de  aluminio. 

This  salt  may  be  manufactured  by  various 
methods  (see  U.S.D.,  19th  ed..  p.  124)  as,  for  ex- 
ample, by  dissolving  aluminum  hydroxide  in  sul- 
furic acid,  but  is  now  obtained  chiefly  as  one  of 
the  by-products  in  the  manufacture  of  soda  from 
cryolite  or  from  bauxite. 

Description. — "Aluminum  Sulfate  occurs  as  a 
white  crystalline  powder,  as  shining  plates,  or  as 
crystalline  fragments,  and  is  stable  in  air.  It  is 
odorless,  and  has  a  sweet  taste,  becoming  mildly 
astringent.  Its  solutions  are  acid  to  litmus.  One 
Gm.  of  Aluminum  Sulfate  dissolves  in  about  1  ml. 
of  water.  It  is  insoluble  in  alcohol."  US.P. 

Standards  and  Tests. — Identification. — A  1 
in  10  aqueous  solution  of  aluminum  sulfate  re- 
sponds to  tests  for  aluminum  and  for  sulfate. 
pH. — The  pH  of  a  1  in  20  solution  is  not  less 
than  2.9.  Alkalies  and  alkaline  earths. — Not  over 
0.4  per  cent  of  residue  is  obtained  on  evaporating 
the  filtrate  from  a  solution  of  aluminum  sulfate 
from  which  the  aluminum  has  been  precipitated 
by  ammonia  T.S.  Ammonium  salts. — Ammonia  is 
not  evolved  on  heating  1  Gm.  of  aluminum  sulfate 
with  10  ml.  of  sodium  hydroxide  T.S.  Arsenic. — 
Aluminum  sulfate  meets  the  requirements  of  the 
test  for  arsenic.  Heavy  metals. — The  limit  is  40 
parts  per  million.  Iron. — A  blue  color  is  not  pro- 
duced immediately  on  adding  0.3  ml.  of  potassium 
ferrocyanide  T.S.  to  20  ml.  of  a  1  in  150  solution 
of  aluminum  sulfate.  U.S.P. 

Assay. — A  sample  of  about  500  mg.  of  alumi- 
num sulfate  is  assayed  as  explained  under  Alum. 
Each  Gm.  of  aluminum  oxide  represents  6.536 
Gm.   of  Ai2(S04)3.18H20.   N.F. 

Uses. — Aluminum  sulfate  has  medicinal  prop- 
erties very  similar  to  those  of  alum.  In  15  per 
cent  concentration  it  is  used  in  perspiration- 
inhibiting  creams ;  it  may  be  used  with  aluminum 
chloride  in  liquid  deodorants.  It  has  been  em- 
ployed in  aqueous  solution  (about  4  or  5  per 
cent)  as  an  antiseptic,  detergent  application  to 
foul  ulcers,  and  as  an  injection  in  fetid  leukor- 
rhea.  In  10  per  cent  aqueous  solution  it  was  used 
by  Deuschle  (Cincinnati  M.  J.,  1943,  23,  578) 
in  sterilization  of  shallow  dental  cavities  and  the 
alveolus  after  tooth  extraction,  the  area  being 
packed  and  the  solution  dispersed  by  the  passage 
of  a  2.5  milliampere  galvanic  current  for  10  min- 
utes through  the  saturated  pack.  Solution  of 
aluminum  sulfate  is  capable  of  dissolving  a  con- 
siderable quantity  of  freshly  precipitated  alumi- 
num hydroxide.  Such  a  solution,  impregnated 
with  benzoin,  has  been  used  as  a  hemostatic  and 
as  a  vaginal  douche  in  leukorrhea,  under  the 
name   of   benzoinated  solution  of  alumina    (for 


Part  I 


Aminacrine    Hydrochloride  61 


method  of  preparation  see  U.S.D.  24th  ed.,  p.  58). 
It  resembles  the  styptic  liquid  of  Pagliari. 

Solutions  of  aluminum  sulfate  in  water  are 
commonly  used,  by  local  application,  in  a  con- 
centration of  5  to  25  per  cent,  |v] 

Storage. — Preserve  "in  well-closed  contain- 
ers." U.S.P. 

Off.  Prep. — Aluminum  Subacetate  Solution, 
U.S.P. 

AMARANTH.     U.S.P. 

F.D.  and  C.  Red  No.  2,  [Amaranthum] 


Nq03S 


N=N 


S03Na 


"Amaranth  contains  not  less  than  94  per  cent 
of  C2oHnN2Na30ioS3,  calculated  on  the  dried 
basis."  U.S.P. 

Amaranth  Color;  Azo  Acid  Rubin  2  B;  Fast  Red  D; 
Bordeaux  S.  Sp.  Amaranto. 

One  of  the  products  obtained  in  the  sulfonation 
of  betanaphthol  is  2-naphthol-3,6-disulfonic  acid, 
a  dye  intermediate  known  as  R-acid,  from  the  red- 
dish color  of  its  azo  dye  derivatives.  By  coupling 
R-acid  with  the  diazo  derivative  of  naphthionic 
acid  (l-naphthylamine-4-sulfonic  acid)  there  re- 
sults the  l-(4-sulfo-l-naphthylazo)-2-naphthol- 
3,6-disulfonic  acid,  of  which  amaranth  is  the  tri- 
sodium  salt. 

Description. — "Amaranth  occurs  as  a  dark 
red  brown  powder.  One  Gm.  of  Amaranth  dis- 
solves in  about  15  ml.  of  water;  it  is  very  slightly 
soluble  in  alcohol."  U.S.P. 

Standards  and  Tests. — Identification. — (1) 
The  color  of  a  1  in  100  solution  of  amaranth, 
when  viewed  through  a  depth  of  1  cm.,  is  vivid 
red;  it  is  not  appreciably  changed  on  adding  hy- 
drochloric acid,  but  is  intensified  on  adding  sodium 
hydroxide  T.S.  (2)  About  50  mg.  of  amaranth 
and  200  mg.  of  powdered  sodium  hydroxide  is 
fused  by  heating  in  a  small  test  tube.  On  adding 
0.5  ml.  of  water  to  the  cooled  residue,  then  a 
moderate  excess  of  diluted  hydrochloric  acid,  and 
warming,  sulfur  dioxide  is  evolved,  which  may  be 
recognized  by  its  odor  and  also  by  testing  the 
vapor  with  starch  iodate  paper.  Loss  on  drying. — 
Not  over  10  per  cent,  when  dried  at  120°  to  con- 
stant weight.  Water-insoluble  substances. — Not 
over  0.5  per  cent.  Metals  precipitated  by  am- 
monia, ammonium  oxalate  and  phosphate. — Not 
more  than  approximately  1  per  cent.  Ether- 
extractable  substances. — Not  over  0.2  per  cent. 
U.S.P. 

Assay. — About  350  mg.  of  amaranth  is  dis- 
solved in  water,  sodium  citrate  is  added,  and  the 
solution  is  titrated  with  0.1  N  titanium  trichlo- 
ride, at  boiling  temperature,  which  reduces  the 
dye  to  a  colorless  or  practically  colorless  deriva- 


tive. Each  ml.  of  0.1  N  titanium  trichloride  repre- 
sents 15.11  mg.  of  C2oHuN2Na30ioS3.  U.S.P. 

Uses. — Amaranth  is  commonly  used  in  the 
dyeing  of  wool  and  silk,  being  an  exceptionally 
fast,  light  color.  Because  of  its  comparatively 
innocuous  character  it  is  also  included  in  the 
U.  S.  Government  list  of  certified  colors  for  foods, 
drugs,  and  cosmetics.  It  holds  its  color  fairly  well 
in  either  acid  or  alkaline  solutions.  For  studies  of 
its  pharmaceutical  uses  see  Pharm.  J.,  1936,  136, 
233,  458,  and  /.  A.  Ph.  A.  Prac.  Ed.,  1941,  2,  398. 

Storage. — Preserve  "in  well-closed  contain- 
ers." U.S.P. 

AMARANTH   SOLUTION.  U.S.P. 

Liquor  Amaranthi 

Dissolve  1  Gm.  of  amaranth  in  sufficient  puri- 
fied water  to  make  100  ml.  U.S.P. 

Description. — "Amaranth  Solution  is  a  clear, 
vivid  red  liquid,  having  but  a  slight  odor."  U.S.P. 

Storage. — Preserve  "in  tight,  light-resistant 
containers."  U.S.P. 

COMPOUND  AMARANTH  SOLUTION. 

N.F. 

Dissolve  100  Gm.  of  caramel  in  500  ml.  of 
purified  water,  add  90  ml.  of  amaranth  solution, 
250  ml.  of  alcohol,  and  enough  purified  water  to 
make  the  product  measure  1000  ml.;  mix  well. 
N.F. 

Alcohol  Content. — From  22  to  25  per  cent, 
by  volume,  of  C2H5OH.  N.F. 

This  solution  is  used  as  a  color  in  several  N.F. 
preparations;  it  replaces  the  compound  cudbear 
tincture  long  used  similarly  but  which  varied  to 
some  extent  in  tinctorial  power. 

Storage. — Preserve  "in  tight,  light-resistant 
containers."  N.F. 

AMINACRINE  HYDROCHLORIDE. 
B.P. 

Aminacrinae  Hydrochloridum 


HCI.H20 


This  antiseptic  dye  is  referred  to  in  the  Ameri- 
can literature  as  9-aminoacridine  hydrochloride, 
but  the  B.P.  describes  it  as  5-aminoacridine  hydro- 
chloride monohydrate,  containing  not  less  than 
98.5  per  cent  of  C13H10N2.HCI  calculated  with 
reference  to  the  substance  dried  to  constant  weight 
at  100°  at  a  pressure  not  exceeding  5  mm.  of 
mercury.  The  substance  may  be  prepared  by  the 
reaction  of  N-phenylanthranilic  acid  with  phos- 
phorus oxychloride,  then  reacting  the  product  with 
ammonium  carbonate  in  phenol. 

Description. — Aminacrine  hydrochloride  oc- 
curs as  a  pale  yellow,  crystalline,  odorless  powder, 
having  a  bitter  taste.  It  is  soluble  in  300  parts  of 
water,  at  20°;  it  is  soluble  in  90  per  cent  alcohol, 
also  in  glycerin;  at  20°  it  is  soluble  in  2000  parts 
of  isotonic  sodium  chloride  solution;  it  is  almost 
insoluble  in  ether  and  in  chloroform. 


62 


Aminacrine    Hydrochloride 


Part   I 


Standards  and  Tests. — Identification. — (1) 
A  saturated  aqueous  solution  is  pale  yellow,  ex- 
hibiting a  greenish-blue  fluorescence;  a  very  di- 
lute solution  has  a  powerful  blue  fluorescence. 
(2)  Aminacrine,  liberated  by  the  addition  of  alkali 
to  a  solution  of  the  salt  and  dried  at  105°  after 
recrystallization  from  dilute  alcohol,  melts  at 
about  235°.  (3)  The  salt  responds  to  tests  char- 
acteristic of  chlorides.  Acidity. — The  pH  of  a  0.2 
per  cent  (w/v)  solution  is  between  5.0  and  6.5. 
Loss  on  drying. — Not  more  than  8.0  per  cent. 
Sulfated  ash. — Not  more  than  0.2  per  cent. 

Assay. — The  assay,  using  about  500  mg.  of 
sample,  is  identical  with  that  specified  for  Pro- 
flavine Hemisuljate.  Each  ml.  of  0.1  M  potassium 
ferricyanide  represnts  69.21  mg.  of  C13H10N2.- 
HC1,  this  equivalent  being  based  on  the  reaction 
of  three  molecules  of  aminacrine  hydrochloride 
with  one  molecule  of  potassium  ferricyanide. 

Uses. — In  vitro  tests  have  demonstrated  that 
the  bacteriostatic  and  bactericidal  powers  of 
aminacrine  hydrochloride  are  slightly  greater  than 
those  of  proflavine;  the  toxicity,  when  injected 
subcutaneously  into  mice,  is  midway  between  that 
of  proflavine  and  of  acriflavine  (Rubbo  et  al., 
Brit.  J.  Exp.  Path.,  1942,  23,  69).  The  same  in- 
vestigators concluded  that  it  is  only  slightly  more 
toxic  to  human  polymorphonuclear  leukocytes 
than  is  proflavine.  Russell  and  Falconer  {Lancet, 
1943,  244,  580)  showed  that  an  isotonic  1:1000 
solution,  buffered  at  pH  6.2,  was  harmless  when 
applied  to  exposed  rabbit's  brain  tissue,  while  the 
same  concentration  of  acriflavine  caused  hemor- 
rhage and  necrosis.  After  an  intensive  study  of 
the  bacteriological  and  pharmacological  proper- 
ties, Ungar  and  Robinson  {Lancet,  1943,  245, 
285;  /.  Pharmacol.,  1944,  80,  217)  concluded  that 
it  was  an  effective  antiseptic  having  certain  ad- 
vantages over  acriflavine  and  proflavine.  The  hy- 
drochloride, in  powder  form,  is  the  least  inhibitory 
to  healing  of  wounds  of  any  of  the  acridine  anti- 
septics, though  Russell  and  Falconer  (loc.  cit.) 
and  Selbie  and  Mcintosh  (/.  Path.  Bad.,  1943, 
55,  477)  could  not  recommend  the  use,  in  powder 
form,  of  any  of  the  salts  of  acridine  antiseptics 
for  prophylactic  treatment  of  fresh  wounds. 

Poate  {Lancet,  1944,  247,  238;  Med.  J.  Aus- 
tralia, 1944,  1,  242)  controlled  sepsis  in  wounds 
in  all  but  5  out  of  120  cases  by  irrigation  with  a 
1:1000  solution,  with  an  emulsion,  or  with  a 
powder  containing  10  to  40  parts  of  sulfanilamide 
to  1  part  of  the  acridine  compound.  The  solution 
appeared  to  be  particularly  effective  against  hemo- 
lytic staphylococci;  against  pyocyaneus  infection 
a  1:1000  solution  in  2  per  cent  acetic  acid  was 
used.  Effective  sterilization  of  skin,  prior  to  sur- 
gical operation,  by  application  of  a  1  per  cent 
solution  in  50  per  cent  alcohol,  was  reported  by 
Bonney  and  Sandeman-Allen  {Brit.  M.  J.,  1944, 
2,  210).  Arden  {Med.  J.  Australia,  1945,  32,  486) 
preferred  local  application  of  9-aminoacridine  hy- 
drochloride {Monocrine)  to  excision  of  contami- 
nated wounds,  even  when  brain  tissue  was  in- 
volved. 

Nemir  {Arch.  Surg.,  1951,  62,  493)  employed 
solutions  containing  0.05  to  0.5  mg.  per  ml.  in 
peritoneal  exudate  following  soiling  with  bowel 
contents;  the  results  were  superior  to  those  ob- 


tained with  1  unit  of  penicillin  and  10  units  of 
streptomycin  per  ml.  or  with  0.1  mg.  of  sulfa- 
diazine per  ml.  In  nontoxic  concentrations  amina- 
crine hydrochloride  inhibited  CI.  welchii,  E.  coli, 
Staph,  aureus,  and  some  streptococci.  As  men- 
tioned under  Sulfanilamide,  a  vaginal  cream  con- 
taining 0.2  per  cent  aminacrine  hydrochloride,  15 
per  cent  of  sulfanilamide,  2  per  cent  of  allantoin, 
and  lactose,  in  a  water-miscible  base  buffered  with 
lactic  acid  to  pH  4.5,  has  been  used  effectively  in 
bacterial  cervicitis  and  vaginitis,  Trichomonas 
vaginalis  vaginitis,  and  in  some  cases  of  monilial 
vaginitis  (Warner,  N.  Y.  State  J.  Med.,  1952,  52, 
1029,  and  others). 

Albert  and  Gledhill  {Lancet,  1944,  1,  759) 
found  that  absorbent  dressings  did  not  interfere 
with  the  action  of  aminacrine. 

AMINOACETIC  ACID.    N.F.,  LP. 

Glycocoll,  Glycine,  [Acidum  Aminoaceticum] 
H2N.CH2.COOH 

"Aminoacetic  Acid,  dried  at  105°  for  2  hours, 
yields  not  less  than  98.5  per  cent  and  not  more 
than  101.5  per  cent  of  C2H5NO2."  N.F.  The  LP. 
requires  not  less  than  98.5  per  cent  of  C2H5O2N, 
calculated  with  reference  to  the  substance  dried 
at  105°  for  2  hours. 

Ger.  Aminoessigsaure;  Glykokoll;  Glycin;  Sp.  Acido 
Aminoacetico. 

Caution. — Glycine  should  not  be  confused  with 
glycin  (/>-hydroxyphenyl-aminoacetic  acid) ,  which 
is  a  poisonous  substance. 

Aminoacetic  acid,  the  simplest  of  the  amino 
acids,  is  found  in  bile  in  combination  with  cholic 
acid.  It  is  a  constituent  of  many  proteins  and  may 
be  obtained  by  the  hydrolysis  of  glue,  gelatin  and 
silk  fibroin;  Bergmann  (/.  Biol.  Chem.,  1938,  122, 
577)  found  that  it  makes  up  one-half  of  the  total 
amino  acids  of  the  last-named  substance. 

Several  processes  for  preparing  aminoacetic  acid 
have  been  patented;  these  include  hydrolysis  of 
glycine  esters  with  organic  acids,  alkaline  hy- 
drolysis of  glycine  ethyl  ester  sulfate,  hydrolysis 
of  methylene-aminoacetonitrile,  electrolytic  re- 
duction of  cyanoformic  ester,  as  well  as  a  method 
involving  hydrolysis  of  neck  ligaments  of  cattle. 
Large  quantities  of  the  acid  may  be  conveniently 
and  economically  prepared,  however,  by  the  reac- 
tion of  chloroacetic  acid  with  excess  ammonia  at 
room  temperature  or  with  ammonium  carbonate 
at  a  temperature  of  60  to  65°.  The  excess  of 
ammonia  is  evaporated  and  the  glycine  crystallized 
after  addition  of  methyl  alcohol;  the  product  is 
purified  by  recrystallization  from  methyl  alcohol- 
water  solution.  For  other  syntheses  of  amino- 
acetic acid  see  Schmidt's  Chemistry  of  the  Amino 
Acids  and  Proteins  (Second  Edition,  1944). 

While  the  formula  of  aminoacetic  acid  is  com- 
monly written  as  H2N.CH2.COOH,  various  physi- 
cal and  chemical  properties  of  the  substance  in- 
dicate that  it  does  not  exist  in  this  form.  It  is 
now  fairly  certainly  established  that  the  tendency 
of  the  carboxyl  group  to  give  up  a  proton  (which 
property  is  characteristic  of  acids)  and  the  tend- 
ency of  the  amino  group  to  accept  a  proton 
(which  property  is  characteristic  of  bases)  results 


Part  I 


Aminoacetic   Acid 


63 


in  the  migration  of  the  proton  (hydrogen  ion) 
from  the  carboxyl  to  the  amino  group,  giving  rise 
to  a  neutral  ion  of  the  composition  H3+N.CH2.- 
COO~.  Such  an  ion  has  been  called  a  "zwitter- 
ion"  (meaning  hybrid  ion)  but  is  better  called 
a  "dipolar  ion."  The  property  of  forming  dipolar 
ions  is  characteristic  of  amino  acids.  Notwith- 
standing this  internal  neutralization  of  amino- 
acetic acid,  the  substance  is  capable  of  acting  as 
an  acid  or  a  base,  depending  on  the  solvent 
medium  and  whether  or  not  another  base  or  acid 
is  present  to  react  with  it.  Thus,  it  forms  a  crys- 
talline salt  with  hydrochloric  acid,  aminoacetic 
acid  hydrochloride,  which  may  be  used  as  a  con- 
venient means  of  administering  the  acid  since  in 
the  body  the  hydrochloric  acid  component  is 
released. 

A  suggested  mechanism  by  which  aminoacetic 
acid  enters  into  the  building-up  of  proteins  is 
presented  in  the  article  on  Amino  Acids,  Part  II. 

Description. — "Aminoacetic  Acid  occurs  as  a 
white,  odorless,  crystalline  powder,  having  a 
sweetish  taste.  Its  solution  is  acid  to  litmus  paper. 
One  Gm.  of  Aminoacetic  Acid  dissolves  in  about 
4  ml.  of  water.  It  is  very  slightly  soluble  in  alco- 
hol and  in  ether."  N.F. 

Standards  and  Tests. — Identification. — (1) 
A  vigorous  evolution  of  colorless  gas  (nitrogen) 
results  when  5  drops  of  diluted  hydrochloric  acid 
and  5  drops  of  a  1  in  2  solution  of  sodium  nitrite 
are  added  to  5  ml.  of  a  1  in  10  solution  of  amino- 
acetic acid.  (2)  A  deep  wine  color  is  produced 
on  adding  1  ml.  of  ferric  chloride  T.S.  to  2  ml.  of  a 

1  in  10  solution  of  aminoacetic  acid;  on  adding  an 
excess  of  diluted  hydrochloric  acid  the  color  dis- 
appears, to  reappear  on  adding  stronger  ammonia 
T.S.  in  excess.  (3)  A  blue  color  is  produced  on 
adding  1  drop  of  liquefied  phenol  and  5  ml.  of 
sodium  hypochlorite  T.S.  to  2  ml.  of  a  1  in  10 
solution  of  aminoacetic  acid.  Loss  on  drying. — 
Not  over  0.2  per  cent,  when  dried  at   105°   for 

2  hours.  Residue  on  ignition. — Not  over  0.1  per 
cent.  Readily  carbonizable  substances. — A  solu- 
tion of  500  mg.  of  the  acid  in  5  ml.  of  sulfuric 
acid  is  colorless.  Chloride. — The  limit  is  70  parts 
per  million.  Sulfate. — The  limit  is  65  parts  per 
million.  Heavy  metals. — The  limit  is  20  parts  per 
million.  Hydrolyzable  substances. — A  1  in  10 
solution  of  aminoacetic  acid  which  has  been  boiled 
for  1  minute  and  then  set  aside  for  2  hours  is  as 
clear  and  mobile  as  the  same  solution  which  has 
not  been  boiled.  N.F. 

For  information  on  the  solubility  of  amino- 
acetic acid  in  mixtures  of  water  and  alcohol  see 
Dunn  and  co-workers  (/.  Biol.  Chem.,  1938,  125, 
309). 

Assay. — About  175  mg.  of  aminoacetic  acid, 
previously  dried  at  105°  for  2  hours,  is  titrated 
with  0.1  A7  sodium  hydroxide  in  the  presence  of 
formaldehyde.  Each  ml.  of  0.1  N  sodium  hy- 
droxide represents  7.507  mg.  of  C2H5NO2.  N.F. 
For  an  explanation  of  the  assay  see  the  following 
monograph.  The  LP.  employs  the  Kjeldahl  method 
of  assay  for  nitrogen. 

Incompatibilities. — The  sparing  solubility  of 
aminoacetic  acid  in  alcoholic  liquids  may  cause 
its  precipitation  from  aqueous  solution  on  the 
addition  of  alcohol.  Ferric  salts  cause  a  wine-red 


color,  destroyed  by  acids;  nitrites  may  react  with 
the  liberation  of  nitrogen.  Grill  (/.  A.  Ph.  A., 
1938,  27,  871)  reported  development  of  a  brown 
color  in  solutions  of  aminoacetic  acid  containing 
low  iso-alcoholic  elixir. 

Uses. — Glycine,  as  such,  is  not  widely  used  in 
therapeutics  but  in  combination  with  other  phar- 
macologic agents  it  is  important.  In  the  metabo- 
lism of  the  body,  aminoacetic  acid  is  involved  in 
the  synthesis  of  body  protein,  creatine,  glycocholic 
acid,  glutathione,  uric  acid,  heme,  etc.  It  converts 
benzoic  acid  to  its  detoxified  derivative  hippuric 
acid. 

Myopathies. — The  theory  originally  put  forth 
by  Thomas  in  1932  that  glycine  was  the  chief 
source  of  the  creatine  of  the  muscles  received 
support  from  the  studies  of  Bloch  and  Schoen- 
heimer  (/.  Biol.  Chem.,  1940,  133,  633;  134, 
785),  but  these  authors  showed  further  that 
methionine  and  arginine  are  also  converted  into 
creatine  (/.  Biol.  Chem.,  1941,  138,  167).  More- 
over, glycine  is  readily  synthesized  by  man  in 
adequate  amounts  (Quick,  /.  Biol.  Chem.,  1931, 
92,  65;  Shemin  and  Rittenberg,  /.  Biol.  Chem., 
1944,  153,  401)  and  it  is  not  an  essential  amino 
acid  in  the  diet  (Rose,  Physiol.  Rev.,  1938,  18, 
109).  In  normal  men  creatine  does  not  appear  in 
the  urine  except  after  violent  muscular  exertion, 
being  excreted  as  a  related  compound  creatinine. 
In  certain  diseases  of  the  voluntary  muscles,  how- 
ever— notably  so-called  progressive  muscular  dys- 
trophy— creatine  does  appear  in  the  urine.  Thomas 
in  1932  tried  glycine  in  this  tragic  disease.  Since 
then  a  number  of  clinicians  reported  favorably  on 
its  effects,  not  only  in  progressive  muscular  dys- 
trophy but  also  in  myasthenia  gravis  (Boothby, 
Proc.  Mayo,  1932,  7,  447),  poliomyelitis  and 
Addison's  disease,  but  others  failed  to  see  any 
marked  benefit  from  the  drug  (J.A.M.A.,  1939, 
113,  559;  and  1942,  119, 1506;  1951,  147,  1185). 
Chaikelis  (Am.  J.  Physiol.,  1941,  133,  578)  re- 
ported that  in  normal  men  it  increases  muscular 
power  and  delays  appearance  of  muscle  fatigue. 
Maison,  however  (J. A.M. A.,  1940,  115,  1439), 
believes  that  the  reported  experiments  dealing 
with  fatigue  are  open  to  criticism.  In  a  well- 
controlled  study  (J.A.M.A.,  1942,  118,  594) 
glycine  failed  to  increase  the  work  capacity  of 
human  subjects.  A  high-protein  diet  seems  prefer- 
able to  this  unessential  amino  acid  and  also  to 
the  incomplete  protein,  gelatin,  which  has  been 
employed  as  a  dietary  source  of  glycine  (about 
25  per  cent). 

Tracer  Studies. — The  ready  incorporation  of 
glycine  into  so  many  essential  compounds  in  the 
body  has  made  this  amino  acid,  when  labeled  with 
the  isotope  C14  (Rittenberg  and  Shemin,  J.  Biol. 
Chem.,  1950,  185,  103;  Barnet  and  Wick,  ibid., 
657)  or  N15  (Shemin  and  Rittenberg,  ibid.,  1945, 
159,  567),  most  useful  in  the  study  of  the  inter- 
mediary metabolism  of  tissue  and  serum  protein, 
hemoglobin,  carbohydrate  and  other  substances. 
Rapid  incorporation  into  serum  and  tissue  pro- 
tein has  been  observed.  Only  a  small  portion, 
varying  with  the  nutritional  status  and  the  pro- 
tein intake,  appears  in  the  urine  during  the  first 
24  hours.  Some  of  the  carbon  is  excreted  as 
carbon  dioxide  by  the  lungs  (Berlin  et  al.,  J.  Clin. 


64 


Aminoacetic   Acid 


Part   I 


Inv.,  1951,  30,  73).  Labeled  glycine  has  been 
employed  to  study  the  life-span  of  erythrocytes 
in  circulating  blood;  the  estimate  of  about  4 
months  made  with  immunological  methods  was 
confirmed.  Tracer  studies  show  also  that  glycine 
is  converted  to  uric  acid  (Benedict  et  al.,  Me- 
tabolism, 1952,  1,  3),  creatinine  (Shemin  and 
Rittenberg,  /.  Biol.  Chem.,  1947,  167,  875)  and 
other  compounds.  Since  nitrogen  excretion  is  in- 
creased by  the  administration  of  cortisone,  feeding 
experiments  with  glycine  labeled  with  N15  were 
conducted  by  Clark  (/.  Biol.  Chem.,  1953,  200, 
69)  to  determine  the  mechanism  of  this  action; 
the  procedure  used  by  Sprinnan  and  Rittenberg 
(ibid.,  1949,  180,  715)  was  used.  It  was  found 
that  the  increased  nitrogen  excretion  during  corti- 
sone therapy  resulted  from  interference  with 
protein  synthesis  in  the  tissues,  with  some  ac- 
cumulation of  amino  acids  in  the  liver.  Studies 
with  glycine  labeled  with  both  C14  and  N15  have 
been  conducted  (Chao  et  al.,  Fed.  Proc,  1952, 
11,  437).  Isotope-labeled  glycine  has  been  em- 
ployed to  study  the  effect  of  steroid  hormones  on 
the  metabolism  of  the  cells  of  the  rat  uterus. 

Peripheral  Vascular  Insufficiency. — Gly- 
cine possesses  the  metabolism-stimulating  action 
of  protein  (so-called  Specific  Dynamic  Action) 
which  amounts  to  about  10  per  cent  of  the  basal 
metabolic  rate).  Since  this  heat  is  dissipated  by 
an  increase  in  peripheral  blood  flow,  Gubner  et  al. 
(Am.  J.  Med.  Sc,  1947,  213,  46)  and  Gustafson 
et  al.  (Surgery,  1949,  25,  539)  prescribed  20  Gm. 
of  glycine  dissolved  in  200  ml.  of  water  by 
mouth  three  times  daily  as  a  vasodilator  in  cases 
of  thromboangiitis  obliterans,  Raynaud's  phe- 
nomenon, arteriosclerosis  and  other  occlusive 
peripheral  vascular  diseases;  beneficial  results 
were  obtained.  The  increase  in  peripheral  blood 
flow  was  greater  than  that  obtainable  with  in- 
gestion of  ethyl  alcohol.  Collentine  (/.  Lab.  Clin. 
Med.,  1948,  33,  1555)  reported  on  the  safety  of 
the  intravenous  administration  of  a  5  or  10  per 
cent  solution  in  isotonic  sodium  chloride  solution 
in  a  dose  of  200  mg.  per  kilogram  of  body  weight 
in  a  period  of  30  minutes.  With  double  this  dose, 
warmth  and  tingling  of  the  extremities,  increased 
salivation,  nausea  and  lightheadedness  were  ex- 
perienced for  about  30  minutes  following  com- 
pletion of  the  injection.  In  two  cases  of  cirrhosis 
of  the  liver,  a  maximum  concentration  of  32  mg. 
per  100  ml.  of  blood  (method  of  Christensen 
et  al,  J.  Biol.  Chem.,  1947,  168,  191)  was  found 
at  the  end  of  the  injection  from  an  initial  con- 
centration of  about  3  mg.  per  100  ml.;  the  maxi- 
mum urinary  excretion  occurred  during  the  half 
hour  of  the  injection  and  the  half  hour  afterward, 
and  the  concentration  in  the  blood  returned  al- 
most to  the  initial  level  in  2>y2  hours. 

Antacid. — A  mixture  of  30  per  cent  amino- 
acetic acid  and  70  per  cent  calcium  carbonate 
(Titralac,  N.N.R.,  Schenley)  produces  an  acid 
neutralization  curve  similar  to  that  of  whole  milk 
(J.A.M.A.,  1950,  152,  991);  absence  of  systemic 
alkalosis  and  acid  "rebound"  is  claimed  and  the 
product  is  recommended  particularly  for  patients 
with  peptic  ulcers  who  are  unable  to  tolerate  milk. 
The  dose  is  1  to  2  tablets,  each  containing  150  mg. 
glycine   and   350  mg.   calcium   carbonate,   taken 


with  water  after  meals  or,  in  more  severe  cases, 
every  hour. 

Dihydroxyaluminum  Aminoacetate  N.F.  is  a 
basic  aluminum  salt  of  this  amino  acid  which  is 
employed  as  an  antacid.  Its  properties  and  uses 
are  described  elsewhere  in  Part  I. 

Other  Uses  and  Combinations. — Because  of 
the  amphoteric  nature  of  aminoacetic  acid  it  may 
be  prepared  in  the  form  of  aminoacetic  acid  hy- 
drochloride, a  crystalline  solid,  which  may  be  used 
as  a  source  of  hydrochloric  acid  for  treatment  of 
achlorhydria  gastrica.  A  dose  of  200  mg.  of  amino- 
acetic acid  hydrochloride  yields  0.6  ml.  of  diluted 
hydrochloric  acid,  which  is  an  average  dose  of  the 
latter.  It  is  of  interest  in  this  connection  that 
aminoacetic  acid  hydrochloride  contains  32.5 
per  cent  of  HC1  as  compared  with  19.9  per  cent 
of  HC1  in  glutamic  acid  hydrochloride,  which  is 
widely  used  as  a  solid  dosage  form  of  hydro- 
chloric acid. 

Glycine  esters  of  various  phenols  are  used  as 
bactericides,  fungicides,  and  insecticides  (Smith 
and  Hansen,  U.  S.  Patent  2,289,599,  July  14, 
1942).  A  water-soluble  glycine  derivative  of  ribo- 
flavin has  been  prepared  (Haas,  U.  S.  Patent 
2,398,706,  April  16,  1946).  A  soluble,  stable,  and 
less  irritating  form  of  theophylline  is  available 
in  the  compound  theophylline  sodium  glycinate 
(q.v.).  Martin  and  Thompson  (U.  S.  Patent 
2,376,795,  May  22,  1945)  used  glycine  to  mini- 
mize untoward  effects  of  sulfapyridine.  Amino- 
acetic acid  is  used  as  an  ingredient  of  S0rensen's 
buffer  mixtures,  along  with  hydrochloric  acid  or 
sodium  hydroxide. 

The  dose  of  aminoacetic  acid  is  from  4  to  30 
Gm.  (approximately  60  grains  to  1  ounce),  with 
the  total  daily  dose  sometimes  exceeding  60  Gm. 

Storage. — Preserve  "in  well-closed  contain- 
ers." N.F. 

AMINOACETIC    ACID    ELIXIR.     N.F. 

Glycine  Elixir,  Glycocoll  Elixir,  [Elixir  Acidi 
Aminoacetici] 

"Aminoacetic  Acid  Elixir  contains,  in  each  100 
ml.,  not  less  than  12.1  Gm.  and  not  more  than 
14.2  Gm.  of  C2H5NO2."  N.F. 

Dissolve  131.5  Gm.  of  aminoacetic  acid  in  700 
ml.  of  purified  water,  add  60  ml.  of  syrup  and  75 
ml.  of  raspberry  syrup,  and  mix  well.  Dissolve 
2  Gm.  of  benzoic  acid  and  0.15  Gm.  of  vanillin 
in  53  ml.  of  alcohol  and  1.5  ml.  of  compound 
orange  spirit  and  add  this  solution  to  that  of  the 
aminoacetic  acid.  Filter,  if  necessary,  and  add 
sufficient  water  to  the  filtrate  to  make  1000  ml. 
N.F. 

Assay. — Exactly  25  ml.  of  aminoacetic  acid 
elixir  is  diluted  to  100  ml.  with  water,  the  solu- 
tion is  decolorized  with  activated  charcoal,  filtered 
and  an  aliquot  portion  of  the  filtrate  neutralized 
with  0.1  AT  sodium  hydroxide,  using  phenolphtha- 
lein  T.S.  as  indicator.  The  volume  of  alkali  re- 
quired is  noted,  but  is  not  used  as  a  quantitative 
measure  of  the  aminoacetic  acid  present  because 
of  the  amphoteric  nature  of  the  acid  resulting 
from  the  presence  of  the  amino  group;  the  alkali 
consumed  is  required  for  the  neutralization  of 
benzoic  acid  and  acid  in  the  raspberry  syrup.  To 
another  aliquot  portion  of  the  filtrate  formalde- 


Part  I 


Aminophylline  65 


hyde  T.S.  is  added,  which  converts  the  NH2.CH2.- 
COOH  to  the  methylene-imino  compound  CH2:- 
N.CH2.COOH  and  permits  titration  of  the  car- 
boxyl  group  with  0.1  N  sodium  hydroxide,  using 
phenolphthalein  T.S.  as  indicator  and  titrating  to 
the  same  color  as  obtained  in  the  first  titration. 
A  blank  titration  to  correct  for  the  acidity  of  the 
formaldehyde  is  performed  and  the  correction 
applied  to  the  titration  in  which  formaldehyde 
was  used.  The  difference  between  the  titrations — 
with  and  without  formaldehyde,  respectively — 
represents  the  amount  of  alkali  required  to  neu- 
tralize the  carboxyl  group  of  the  aminoacetic  acid. 
Each  ml.  of  0.1  N  sodium  hydroxide  represents 
7.507  mg.  of  C2H5NO2.  N.F.  This  titration  is  a 
modification  of  S0renson's  Formol  Method  for 
the  estimation  of  amino  acids.  For  further  dis- 
cussion of  this  assay  see  Green,  Bull.  N.  F. 
Comm.,  1945,  13,  84. 

Alcohol  Content. — From  5  to  7  per  cent,  by 
volume,  of  C2H5OH.  N.F. 

The  average  dose  of  this  elixir  is  15  ml.  (ap- 
proximately 4  fluidrachms),  representing  about  2 
Gm.  of  aminoacetic  acid. 

Storage. — Preserve  "in  tight  containers." 
N.F. 

AMINOPHYLLINE.     U.S.P.,  B.P.,  LP. 

Theophylline  Ethylenediamine,  [Aminophyllina] 
(C7H8N402)2C2H4(NH2)2.2H20 

"Aminophylline  contains  not  less  than  75  per 
cent  and  not  more  than  82  per  cent  of  anhydrous 
theophylline  (C7H8N4O2),  and  not  less  than  12.3 
per  cent  and  not  more  than  13.8  per  cent  of 
ethylenediamine  (C2H8N2)."  U.S.P.  The  B.P. 
and  LP.  requirements  are  identical  with  those 
of  the  U.S.P. 

The  B.P.  states  that  aminophylline  may  be 
prepared  by  dissolving  theophylline  in  ethylene- 
diamine  and  evaporating  the  solution  to  dryness. 
It  is  reported  that  the  compound  contains  a  mix- 
ture of  two  double  salts,  the  one  consisting  of 
one  molecule  of  theophylline  combined  with  one 
molecule  of  ethylenediamine,  the  other  of  one 
molecule  of  theophylline  combined  with  two 
molecules  of  ethylenediamine. 

Description.  —  "Aminophylline  occurs  as 
white  or  slightly  yellowish  granules  or  powder, 
possessing  a  slight  ammoniacal  odor  and  a  bitter 
taste.  Upon  exposure  to  air  it  gradually  loses 
ethylenediamine  and  absorbs  carbon  dioxide  with 
the  liberation  of  free  theophylline.  Its  solutions 
are  alkaline  to  litmus.  One  Gm.  of  Aminophylline 
dissolves  in  about  5  ml.  of  water  but  owing  to 
hydrolysis  separation  of  crystals  of  less  aminated 
theophylline  begins  in  a  few  minutes,  these  crys- 
tals dissolving  on  the  addition  of  a  small  amount 
of  ethylenediamine.  When,  however,  1  Gm.  is 
dissolved  in  25  ml.  of  water  the  solution  remains 
clear.  It  is  insoluble  in  alcohol  and  in  ether." 
U.S.P. 

Standards  and  Tests. — Identification. — To  a 
solution  of  1  Gm.  of  aminophylline  in  20  ml.  of 
water  add,  while  stirring  constantly,  1  ml.  of 
diluted  hydrochloric  acid;  filter  the  precipitate, 
wash  it  with  small  portions  of  cold  water,  and 
dry  it  at  105°  for  1  hour:  the  substance  responds 


to  identification  tests  (1)  and  (2)  under  The- 
ophylline and  melts  between  270°  and  274°. 
Residue  on  ignition. — Not  over  0.15  per  cent. 
U.S.P. 

Assay. — For  theophylline. — A  sample  of 
about  250  mg.  of  aminophylline  is  dissolved  in 
water  containing  ammonia,  a  measured  excess  of 
0.1  N  silver  nitrate  is  added  to  precipitate  silver 
theophylline.  The  mixture  is  filtered  through  a 
filtering  crucible,  the  precipitate  is  washed  with 
water,  and  the  excess  of  silver  ion  in  the  filtrate 
is  determined  by  titration  with  0.1  iV  ammonium 
thiocyanate  in  the  presence  of  nitric  acid  and 
using  ferric  ammonium  sulfate  T.S.  as  indicator. 
Each  ml.  of  0.1  N  silver  nitrate  represents  18.02 
mg.  of  C7H8N4O2.  For  ethylenediamine. — A  solu- 
tion of  about  500  mg.  of  aminophylline  is  titrated 
with  0.1  Af  hydrochloric  acid,  using  methyl  orange 
T.S.  as  indicator.  Each  ml.  of  0.1  N  acid  repre- 
sents 3.005  mg.  of  C2H8N2.  U.S.P. 

The  B.P.  assays  for  theophylline  by  dissolving 
about  500  mg.  of  aminophylline  in  20  ml.  of 
distilled  water,  neutralizing  the  solution  with 
0.5  N  hydrochloric  acid  using  bromocresol  green 
indicator  and  saturating  the  solution  with  sodium 
chloride,  then  extracting  the  theophylline  with  a 
mixture  of  3  volumes  of  chloroform  and  1  volume 
of  isopropyl  alcohol.  The  solvent  is  evaporated, 
and  the  residue  is  dried  to  constant  weight  at 
105°.  The  assay  for  ethylenediamine  is  similar 
to  that  of  the  U.S.P.  The  LP.  assays  are  practi- 
cally the  same  as  those  of  the  U.S.P. 

Incompatibilities.  —  Alkaline  in  reaction, 
aminophylline  exhibits  the  incompatibilities  of 
alkalies.  When  in  sufficiently  concentrated  solu- 
tion the  theophylline  in  this  salt  is  precipitated 
by  acids.  On  exposure  to  air  it  gradually  absorbs 
carbon  dioxide  with  liberation  of  theophylline. 
With  lactose,  a  yellow  to  brown  color  develops 
on  standing. 

Uses. — Aminophylline  has  the  general  physio- 
logical properties  of  theophylline.  Its  chief  appli- 
cations in  clinical  medicine  depend  upon  its  modi- 
fication of  blood  flow,  its  relaxation  of  the 
bronchial  and  other  smooth  musculature,  its  diu- 
retic action  and  its  ability  to  antagonize  histamine. 

Action. — It  has  been  shown  by  Schack  and 
Waxier  (/.  Pharmacol.,  1949,  97,  283)  that  the- 
ophylline is  restricted  to  blood  plasma;  it  does 
not  penetrate  the  red  cell  membrane  and  is  bound 
only  slightly  to  blood  proteins.  Further,  it  appears 
to  be  bound  only  slightly  to  tissue  proteins.  They 
concluded  that  its  therapeutic  effect  is  closely 
related  to  the  level  in  the  blood.  Based  upon  this 
finding  and  because  there  is  conflicting  opinion  as 
to  the  therapeutic  effectiveness  of  this  drug, 
Waxier  and  Schack  (J.A.M.A.,  1950,  143,  736) 
studied  the  blood  theophylline  levels  after  admin- 
istration of  various  doses  of  aminophylline  by 
the  intravenous,  intramuscular,  oral  and  rectal 
routes.  Following  intravenous  injection  of  250  mg. 
of  aminophylline  the  blood  concentration  falls 
progressively  to  approximate  zero  after  9  hours. 
Sustained  blood  levels  followed  intramuscular  in- 
jection of  500  mg.,  appreciable  levels  persisting 
for  13  hours.  They  noted  that  this  dosage  given 
intramuscularly  produced  values  about  twice  as 
high  as  a  dose  of  250  mg.,  persisted  about  twice 


66  Aminophylline 


Part   I 


as  long,  and  was  no  more  painful  than  the  smaller 
dose.  Theophylline  appeared  in  circulating  blood 
within  15  minutes  after  ingestion  of  an  uncoated 
tablet  containing  200  mg.,  significant  levels  per- 
sisting for  9  hours.  There  was  a  delay  of  2  hours 
after  oral  ingestion  of  enteric-coated  tablets  be- 
fore the  drug  was  demonstrable  in  the  blood 
plasma,  significant  levels  persisting  7  hours  after 
a  dose  of  200  mg.  and  10  hours  with  a  300  mg. 
dose.  Suppositories  containing  500  mg.  produced 
widely  varying  values. 

Wechsler  et  al.  (J.  Clin.  Inv.,  1950,  29,  28) 
studied  the  cerebral  circulation  and  metabolism 
following  intravenously  administered  aminophyl- 
line and  demonstrated  conclusively  that  it  results 
in  diminished  cerebral  blood  flow  due  to  increased 
cerebrovascular  resistance.  There  was  a  drop  in 
arterial  carbon  dioxide  tension  and  a  rise  in  arte- 
rial pH.  They  were  of  the  opinion  that  aminophyl- 
line constricts  the  cerebral  vessels,  decreasing 
cerebral  blood  flow,  increasing  carbon  dioxide 
tension  of  the  brain,  thus  providing  a  stimulus 
for  hyperventilation,  as  reflected  by  the  rising 
pH.  Moyer  et  al.  (J.  Clin.  Inv.,  1952,  31,  267) 
pointed  out  that  the  arrest  of  Cheyne-Stokes 
respiration  after  aminophylline  cannot,  therefore, 
result  from  an  increase  of  cerebral  blood  flow, 
but  is  probably  due  either  to  a  direct  stimulating 
effect  on  the  respiratory  center  or  an  indirect 
effect  secondary  to  the  depressed  cerebral  circu- 
lation and  resultant  rise  in  tissue  carbon  dioxide 
of  the  medulla.  They  found  no  difference  in  the 
cerebral  hemodynamic  response  to  aminophylline 
of  patients  in  cardiac  failure  exhibiting  Cheyne- 
Stokes  respiration  and  those  with  regular  respi- 
ration. 

Leroy  and  Speer  (/.  Pharmacol.,  1940,  69,  45) 
found  aminophylline  to  be  twice  as  active  as  the- 
ophylline sodium  in  dilating  the  coronary  vessels. 
Hanzlik  and  Moy  (Standford  M.  Bull.,  1945,  3, 
127),  in  experiments  on  dogs,  found  that  intrave- 
nous aminophylline  inhibits  coronary  constriction 
produced  by  posterior  pituitary  solution,  conclud- 
ing that  its  effects  are  fundamentally  vascular 
rather  than  a  direct  stimulation  of  the  myo- 
cardium. Stewart  (Cardiac  Therapy,  19520  p.  27) 
states  that  aminophylline  induces  its  benefit  in 
pulmonary  edema  by  increasing  cardiac  output, 
probably  by  direct  action  on  the  heart  muscle, 
and  by  lowering  the  venous  pressure.  Escher 
et  al.  (Fed.  Proc,  1948,  7,  31,  part  I)  demon- 
strated that  in  normal  human  subjects  rapid  in- 
travenous administration  of  aminophylline  pro- 
duced a  significant  increase  in  cardiac  output 
lasting  10  to  20  minutes,  paralleling  a  brief  in- 
crease in  renal  plasma  flow;  glomerular  filtration 
rate  remained  high  for  as  long  as  one  hour  despite 
a  fall  in  renal  plasma  flow  to  below  control  levels. 
In  chronic  congestive  heart  failure  it  produces  a 
marked  increase  in  cardiac  output  lasting  as  long 
as  one  hour.  It  has  been  demonstrated  by  Segal 
and  associates  (/.  Clin.  Inv.,  1949,  28,  1190)  that 
aminophylline  given  intravenously  provides  im- 
mediate protection  against  the  bronchospastic  ef- 
fect of  intravenously  administered  histamine  or 
methacholine.  The  drug  is  a  gastric  irritant  and 
it  has  been  shown  by  Krasnow  et  al.  (Proc.  S. 
Exp.  Biol.   Med.,   1949,   71,   335)    to  stimulate 


production  of  free  hydrochloric  acid  in  the  stom- 
ach after  intravenous   administration. 

Therapeutic  Uses. — Aminophylline  is  valuable 
in  treating  bronchial  asthma,  particularly  by  the 
intravenous  route,  and  is  often  effective  in  cases 
of  status  asthmaticus  in  patients  who  have  become 
refractory  to  epinephrine  (see  Herrmann  and 
Aynesworth,  J.  Lab.  Clin.  Med.,  1937,  23,  135). 
It  is  likewise  beneficial  in  asthmatic  bronchitis 
and  unresolved  pneumonia.  Barach  (J. A.M. A., 
1945,  128,  589)  has  obtained  relief  of  bronchial 
spasm  within  10  to  30  minutes  following  rectal 
instillation  of  aminophylline  solution.  This  mode 
of  administration  is  advantageous  in  that  it  may 
be  used  by  nurses  or  patients  themselves.  Accord- 
ing to  Waldbott  (I.A.M.A.,  1945,  128,  1205) 
sensitivity  to  this  drug  has  never  been  demon- 
strated. Barach  also  found  (I.A.M.A.,  1951,  147, 
730)  that  for  palliative  therapy  in  patients  with 
bronchial  asthma  or  the  bronchospastic  type  of 
chronic  hypertrophic  pulmonary  emphysema  in 
the  absence  of  status  asthmaticus,  aminophylline 
in  doses  of  200  to  300  mg.  is  the  most  satisfac- 
tory oral  medication  for  relief  of  bronchospasm. 
For  maximal  effect  it  must  be  given  when  the 
stomach  is  empty;  if  nausea  results  it  may  be 
relieved  by  two  teaspoonfuls  of  aluminum  hy- 
droxide gel.  Whitfield  et  al.  (Lancet,  1951,  260, 
490)  found  it  valueless  in  emphysema  in  the  ab- 
sence of  bronchospasm.  Kugelmass  (J.A.M.A., 
1951,  147,  1240)  used  aminophylline  to  relax 
the  bronchial  and  esophageal  musculature  to  dis- 
lodge foreign  bodies  inspired  or  swallowed  by 
children,  avoiding  the  need  for  endoscopy;  he 
gave  250  mg.  in  a  solution  instilled  rectally. 
Taplin  et  al.  (Ann.  Allergy,  1949,  7,  513)  found 
that  aminophylline  or  theophylline-lactose  powder, 
in  particle  sizes  of  0.5  to  5  n  in  diameter,  when 
given  by  inhalation  in  a  dosage  of  60  mg.,  will 
relieve  bronchial  spasm  in  a  majority  of  patients 
almost  immediately,  but  for  a  somewhat  shorter 
period  than  with  intravenous  administration.  They 
noted  no  systemic  vasomotor,  allergic  or  local 
irritative  effects. 

The  vasodilator  action  of  aminophylline  is 
recommended  in  recent  myocardial  infarction  by 
Mikotoff  and  Katz  (Am.  Heart  J.,  1945,  30,  215). 
Bakst  et  al.  (ibid.,  1948,  36,  527)  found  that 
intravenous  injection  of  240  mg.  of  aminophyl- 
line increases  the  capacity  for  effort  without  pain 
in  patients  with  angina  of  effort.  It  is  widely 
used  in  patients  with  coronary  artery  disease 
in  doses  of  100  to  200  mg.  3  or  4  times  daily  by 
mouth.  Russek  et  al.  (J.A.M.A.,  1953,  153,  207) 
compared  the  ability  of  various  drugs  to  modify 
the  electrocardiographic  response  to  standard  exer- 
cise (Master  two-step  test)  in  carefully  selected 
patients  with  coronary  artery  disease.  They  found 
that  aminophylline  in  doses  of  500  mg.  adminis- 
tered intravenously  or  400  mg.  by  the  oral  route 
produced  only  a  slight  or  insignificant  effect.  Its 
use  is  recommended  in  treatment  of  pulmonary 
edema,  250  or  500  mg.  being  injected  by  vein. 
Similar  amounts  are  used  at  bedtime  to  prevent 
occurrence  of  nocturnal  dyspnea.  Suppositories 
containing  500  mg.  may  be  substituted  for  this 
purpose.  Kissin  et  al.  (Angiology,  1951,  2,  217) 
found  an  average  improvement  in  exercise  toler- 


Part  I 


Aminophylline  67 


ance  of  42  per  cent  in  subjects  with  intermittent 
claudication  due  to  obliterating  arteriosclerosis, 
following  intravenous  administration  of  a  dose 
of  240  mg.  Rickles  (/.  Florida  M.  Assn.,  1951, 
38,  263)  obtained  relief  of  arterial  spasm  in  simi- 
lar cases  by  direct  injection  of  aminophylline  into 
the  femoral  artery,  with  no  untoward  results. 
Mover  and  associates  (Am.  J.  Med.  Sc,  1952, 
224,  377)  found  the  drug  useful  in  relieving 
hypertensive  headaches,  the  dosage  being  500 
mg.  intravenously.  Mainzer  (Schweiz.  med. 
Wchnschr.,  1949,  79,  108)  found  intravenous 
doses  of  240  mg.  to  be  of  benefit  in  treatment 
of  cerebral  hemorrhage. 

Aminophylline  was  the  only  injectable  diuretic 
preparation  prior  to  the  introduction  of  the 
organic  mercurials.  Vogl  and  Esserman  {J. A.M. A., 
1951,  147,  625)  called  attention  to  the  fact  that 
in  addition  to  increasing  the  effective  renal  blood 
flow  and  glomerular  filtration  rate  it  inhibits 
renal  tubular  reabsorption,  the  latter  being  largely 
responsible  for  its  diuretic  effect.  Unlike  the  or- 
ganic mercurial  diuretics,  however,  it  does  not 
produce  demonstrable  damage  to  the  tubular 
epithelium.  They  evolved  a  schedule  using  a  mer- 
curial injection  intermittently  every  third  day, 
with  multiple  daily  aminophylline  injections  to 
potentiate  and  maintain  diuresis  in  patients  with 
advanced  congestive  heart  failure  who  are  ap- 
parently refractory  to  mercurial  diuretics. 

Cole  (Am.  J.  Surg.,  1946,  72,  719)  reported 
that  intravenous  administration  of  500  mg.  of 
aminophylline  produced  in  9  out  of  10  patients 
relief  from  biliary  colic  within  5  to  7  minutes. 
Seneque  et  al.  (J.  de  Chirurgie,  1952,  68,  340) 
found  that  it  facilitates  passage  of  residual  biliary 
calculi  from  the  common  bile  duct  following 
biliary  surgery  and  in  conjunction  with  Pribam's 
method  of  stimulating  the  flow  of  bile.  Anderson 
and  Mclntyre  (Nebr.  State  M.  J.,  1949,  34,  17) 
found  oral  aminophylline  useful  in  treating  pri- 
mary dysmenorrhea.  Epstein  (Arch.  Dermat. 
Syph.,  1948,  58,  47)  observed  aminophylline,  in- 
travenously administered  in  a  dose  of  500  mg. 
in  20  ml.  of  diluent,  to  give  immediate  relief  in 
patients  with  acute  pruritic  dermatoses. 

Summary. — Aminophylline  is  used  in  treat- 
ment of  bronchial  asthma  and  other  bronchospas- 
tic  conditions,  cardiac  asthma  and  pulmonary 
edema,  coronary  artery  disease,  obliterating  arte- 
riosclerosis, hypertensive  headache  and  cerebral 
hemorrhage,  as  a  diuretic  in  congestive  cardiac 
failure  either  alone  or  to  potentiate  the  effect  of 
mercurial  diuretics,  in  biliary  colic  and  in  various 
acute  pruritic  dermatoses.  lYJ 

Comparison  of  Routes  of  Administration. 
— Rectal  instillation  of  an  aqueous  solution  of 
aminophylline  results  in  almost  as  rapid  absorp- 
tion as  does  intravenous  injection  (Barach,  Bull. 
N.  Y.  Acad.  Med.,  1944,  20,  538) ;  rectal  adminis- 
tration avoids  the  infrequent  but  serious  instances 
of  vascular  collapse  or  fatal  cardiac  response 
which  may  follow  intravenous  administration.  Ab- 
sorption from  rectal  suppositories  is  uncertain, 
occasionally  producing  blood  theophylline  levels 
comparable  to  those  obtained  by  intravenous  in- 
jection of  the  same  dose  of  aminophylline  but 
generally  yielding  low  levels.  Prigal  et  al.  (J.  Al- 


lergy, 1946,  17,  172)  found  suppositories  con- 
taining aminophylline  and  pentobarbital  sodium 
to  relieve  asthma  in  about  half  the  time  required 
for  aminophylline  alone.  Oral  administration  of 
aminophylline  is  less  effective  than  when  the 
drug  is  given  by  the  intravenous  route  or  when 
it  is  instilled  rectally  as  an  aqueous  solution, 
principally  because  the  majority  of  patients  de- 
velop gastrointestinal  disturbances  after  pro- 
longed use.  Enteric-coated  tablets  have  been  em- 
ployed to  overcome  this  disadvantage  and,  re- 
cently, it  has  been  observed  that  simultaneous 
administration  of  aluminum  hydroxide  decreases 
the  incidence  of  gastrointestinal  disturbances  in 
most  patients  to  such  a  degree  that  sufficient 
aminophylline  may  be  given  orally  to  produce 
levels  of  theophylline  in  the  blood  which  are 
comparable  to  those  obtained  by  intravenous  ad- 
ministration (Cronheim  et.  al.,  Postgrad.  Med., 
1953,  13,  432);  the  aluminum  hydroxide  appears 
not  to  alter  the  rate  or  the  degree  of  absorption 
of  aminophylline,  as  compared  with  tablets  of 
aminophylline  by  itself. 

Toxicology. — Scherf  and  Schlachman  (Am. 
J.  Med.  Sc,  1946,  212,  83)  observed  diminished 
prothrombin  time  in  patients  to  whom  aminophyl- 
line was  administered  intravenously.  It  has  been 
believed  that  this  effect,  shared  by  other  methyl- 
xanthines,  may  augment  the  risk  of  thrombosis 
in  certain  patients  receiving  aminophylline  or 
kindred  drugs.  However,  studies  by  Blood  and 
Patterson  (Proc.  S.  Exp.  Biol.  Med.,  1948,  69, 
130)  and  by  Holland  and  Gross  (/.  Iowa  M.  Soc, 
38,  183)  indicate  that  oral  or  intravenous  admin- 
istration of  aminophylline  produces  no  statisti- 
cally significant  changes  in  clotting  time  or  plasma 
prothrombin  time.  Studies  by  Overman  and 
Wright  (Am.  Heart  J.,  1950,  39,  65)  of  the  ef- 
fects of  oral  ingestion  of  the  drug  led  them  to 
the  same  conclusion. 

Intravenous  injections  must  be  given  very 
slowly,  minimum  time  being  4  to  5  minutes,  and 
the  solution  should  be  warmed  to  body  tempera- 
ture before  use.  Rapid  administration  may  lead 
to  peripheral  vascular  collapse.  In  at  least  6  re- 
ported instances  (see  Bresnick  et  al.,  J.A.M.A., 
1948,  136,  397)  sudden  death  has  followed  in- 
travenous administration.  In  each  instance  there 
was  evidence  of  myocardial  disease  and  the  sud- 
denness of  death  suggested  the  probability  that 
cardiac  standstill  or  ventricular  fibrillation  had 
occurred.  Excessive  cerebral  stimulation  may  re- 
sult in  wakefulness,  vertigo,  vomiting,  hyperpnea 
and  even  generalized  convulsions. 

Dose. — The  usual  oral  dose  of  aminophylline 
is  200  mg.  (approximately  3  grains)  3  times  daily, 
with  a  range  of  100  to  200  mg.;  the  maximum 
safe  dose  is  200  mg.  and  the  total  dose  in  24 
hours  should  generally  not  exceed  600  mg.  When 
aluminum  hydroxide  is  given  simultaneously 
larger  doses  of  aminophylline  may  be  tolerated; 
Cronheim  et  al.  (loc.  cit.)  found  most  of  their 
patients  to  tolerate  doses  of  1  to  1.6  Gm.  (15  to 
24  grains),  which  produced  a  reliable  diuretic 
effect,  and  some  as  much  as  2.4  Gm.  (36  grains) 
of  aminophylline  per  day  when  thus  adminis- 
tered. Per  rectum,  the  usual  dose  is  500  mg. 
(approximately  lYz  grains)   1  or  2  times  daily, 


68  Aminophylline 


Part   I 


with  a  range  of  250  to  500  mg.;  the  maximum 
safe  dose  is  500  mg.  and  the  total  dose  in  24 
hours  should  not  exceed  1  Gm.  By  intravenous 
injection,  the  usual  dose  is  500  mg.  (approxi- 
mately lx/z  grains)  up  to  3  times  daily,  with  a 
range  of  250  to  500  mg.;  the  maximum  safe  dose 
is  500  mg.  and  the  total  dose  in  24  hours  should 
not  exceed  1.5  Gm. 

Storage. — Preserve  "in  tight  containers." 
U.S.P. 

AMINOPHYLLINE    INJECTION. 
U.S.P.  (B.P.,  LP.) 

[Injectio  Aminophyllinae] 

"Aminophylline  Injection  is  a  sterile  solution 
of  aminophylline  in  water  for  injection.  It  con- 
tains not  less  than  93  per  cent  and  not  more 
than  107  per  cent  of  the  labeled  amount  of 
C16H24N10O4.2H2O.  For  the  purpose  of  stabiliza- 
tion, Aminophylline  Injection  may  contain  added 
freshly  distilled  ethylenediamine  solution  amount- 
ing to  not  more  than  60  mg.  of  C2H8N2  for  each 
1  Gm.  of  aminophylline."  U.S.P. 

The  B.P.  defines  Injection  of  Aminophylline  as 
a  sterile  solution  of  aminophylline  in  water  for 
injection  free  from  carbon  dioxide;  ethylenedia- 
mine may  be  added  to  aid  solution,  provided  the 
pH  of  the  solution  does  not  exceed  9.6.  The  solu- 
tion is  directed  to  be  sterilized  by  heating  in  an 
autoclave,  or  by  filtration  through  a  bacteria- 
proof  filter.  The  content  of  anhydrous  theophyl- 
line is  not  less  than  71.0  per  cent  and  not  more 
than  86.0  per  cent  of  the  labeled  content  of 
aminophylline.  The  LP.  limits  for  anhydrous 
theophylline  are  73.0  and  83.0  per  cent,  respec- 
tively; for  ethylenediamine  (C2H8X2)  the  limits 
are  12.3  and  19.8  per  cent,  respectively. 

B.P.  Injection  of  Aminophylline;  Injectio  Theophyl- 
linae  cum  .SSthylenediamina.  LP.  Injection  of  Amino- 
phylline; Injectio  Aminophyllini.  Sp.  Inyeccion  de 
Aminofilina. 

The  U.S.P.  permits  an  inordinate  excess  of 
ethylenediamine  (43  per  cent  above  the  upper 
limit  provided  under  Aminophylline)  to  be  used 
"for  the  purpose  of  stabilization."  If  the  amino- 
phylline and  the  injection  are  carefully  prepared 
so  as  to  prevent  absorption  of  carbon  dioxide, 
even  the  most  concentrated  injection  employed 
clinically  may  be  made  with  at  most  only  a  frac- 
tion of  the  permitted  excess  of  ethylenediamine. 

For  uses  and  dose  see  under  Aminophylline. 

Storage. — Preserve  "in  single-dose  contain- 
ers, preferably  of  Type  I  glass."  U.S.P. 

Usual  Sizes. — 2  ml.  containing  500  mg.  (ap- 
proximately 7^2  grains)  for  intramuscular  use; 
10  ml.  or  20  ml.  containing  respectively  250  mg. 
or  500  mg.  (approximately  4  or  7^  grains)  for 
intravenous  use. 

AMINOPHYLLINE  SUPPOSITORIES. 
U.S.P. 

[Suppositoria  Aminophyllinae] 

"Aminophylline  Suppositories  contain  not  less 
than  90  per  cent  and  not  more  than  110  per  cent 
of  the  labeled  amount  of  C16H24X10O4.2H2O." 
U.S.P. 

While  the  U.S.P.  does  not  specify  the  supposi- 


tory base  which  may  be  employed,  a  number  of 
the  products  on  the  market  are  stated  to  be  made 
with  a  Carbowax  base;  one  such  base  may  be 
prepared  by  melting  together  1  part  of  Carbowax 
4000  (polyethylene  glycol  4000,  U.S.P.  XV) 
and  2  to  3  parts  of  Carbowax  1540.  Such  a  base 
will  not  melt  at  body  temperature  but  will  gradu- 
ally release  dispersed  medication  when  sufficient 
moisture  is  absorbed  by  the  suppository,  following 
insertion  in  the  rectum,  to  dissolve  the  base. 

For  uses  and  dose  see  under  Aminophylline. 

Storage. — Preserve  "in  well-closed  containers 
in  a  cold  place."  U.S.P. 

Usual  Size. — 500  mg.  (approximately  l1/* 
grains)  of  aminophylline. 

AMINOPHYLLINE  TABLETS. 
U.S.P.  (B.P.,  LP.) 

[Tabellae  Aminophyllinae] 

"Aminophylline  Tablets  contain  not  less  than 
93  per  cent  and  not  more  than  107  per  cent  of 
the  labeled  amount  of  C16H24X10O4.2H2O." 
U.S.P.  The  B.P.  requires  the  content  of  anhy- 
drous theophylline  to  be  not  less  than  67.5  per 
cent  and  not  more  than  86.0  per  cent,  and  the 
content  of  ethylenediamine  to  be  not  less  than 
11.1  per  cent  and  not  more  than  15.2  per  cent,  of 
the  labeled  amount  of  aminophylline.  The  LP. 
requires  not  less  than  73.0  per  cent  and  not  more 
than  84.0  per  cent  of  anhydrous  theophylline. 

B.P.  Tablets  of  Aminophylline;  Tabellae  Theophyllinae 
cum  iEthylenediamina.  LP.  Compressi  Aminophyllini. 
Sp.  Tablet  as  de  Aminofilina. 

Storage. — Preserve  "in  tight  containers." 
U.S.P. 

Usual  Sizes. — 100  and  200  mg.  (approxi- 
mately \y2  and  3  grains),  enteric  coated  tablets 
or  tablets  containing  aluminum  hydroxide  being 
generally  preferred  to  avoid  gastric  irritation. 
Tablets  containing  aminophylline  and  phenobar- 
bital  are  frequently  prescribed. 

AMINOPYRINE.     X.F.  (LP.) 

Amidopyrine,  [Aminopyrina] 


CH, 


./ 


CH, 


lX3 


(CH3)2N  X0 

The  LP.  defines  Amidopyrine  as  2  :3-dimethyl- 
4-dimethylamino-l -phenyl- 5-pyrazoIone. 

LP.  Amidopyrine,  Amidopyrinum.  Pyramidon  (.Win- 
throp),  Dimethylamino  Antipyrine.  Fr.  Dimethylamino- 
phenyldimethylpyrazolone.  C-er.  Dimethylamino-phenyldi- 
methylpyrazolon.  It.  Fenil-dimetil-dimetilamido-isopira- 
zolone.  Sp.  Aminoantipirina ;  Aminopirina;  Amidopirina. 

This  compound,  first  prepared  in  1893,  may  be 
regarded  as  a  derivative  of  antipyrine  in  which  a 
hydrogen  atom  of  the  pyrazolone  group  is  re- 
placed by  a  dimethylamino  or  N(CHs)2  group. 
It  is  designated  as  1.5-dimethyl-4-dimethylamino- 
2-phenyl-3-pyrazolone  according  to  the  standard 
United  States  nomenclature.  Aminopyrine  is 
manufactured  by  the  reduction  of  isonitrosoanti- 
pyrine  with  zinc  and  subsequent  methylation  of 


Part  I 


Aminopyrine   Elixir  69 


the  resulting  4-amino-antipyrine  by  means  of 
methyl  iodide  or  dimethyl  sulfate.  Because  of  the 
difficulty  of  directly  methylating  the  aminoanti- 
pyrine  various  means  of  indirectly  accomplishing 
this  have  been  employed. 

Description. — "Aminopyrine  occurs  as  color- 
less or  white,  small  crystals,  or  as  a  white,  crystal- 
line powder.  It  is  odorless  and  is  stable  in  air 
but  is  affected  by  light.  Its  solutions  are  alkaline 
to  litmus  paper.  One  Gm.  of  Aminopyrine  dis- 
solves in  18  ml.  of  water,  in  1.5  ml.  of  alcohol, 
in  1  ml.  of  chloroform,  and  in  13  ml.  of  ether. 
Aminopyrine  melts  between  106.5°  and  109°." 
N.F. 

Standards  and  Tests. — Identification. — (1) 
A  bluish  violet  color  develops  on  adding  3  drops 
of  diluted  hydrochloric  acid  and  1  ml.  of  ferric 
chloride  T.S.  to  5  ml.  of  a  1  in  25  solution  of 
aminopyrine;  the  color  changes  to  violet  red  on 
adding  a  few  drops  of  diluted  sulfuric  acid.  (2) 
A  deep  violet  color,  changing  to  a  grayish  black 
precipitate  of  silver,  is  formed  on  adding  5  drops 
of  silver  nitrate  T.S.  to  5  ml.  of  a  1  in  25  solu- 
tion of  aminopyrine.  (3)  A  dark  blue  color  or 
precipitate  is  immediately  formed  when  a  1  in  25 
solution  of  aminopyrine  is  added  to  a  freshly  pre- 
pared potassium  ferricyanide  T.S.  containing 
some  ferric  chloride  (difference  from  antipyrine). 
Loss  on  drying. — Not  over  1  per  cent,  when  dried 
at  60°  for  2  hours.  Residue  on  ignition. — Not 
over  0. 1 5  per  cent.  Chloride. — A  purple  color,  but 
no  turbidity,  is  immediately  produced  on  adding 
silver  nitrate  T.S.  to  a  solution  of  aminopyrine 
acidified  with  nitric  acid.  Heavy  metals. — The 
limit  is  20  parts  per  million.  Readily  carbonizable 
substances. — A  solution  of  100  mg.  of  aminopy- 
rine in  1  ml.  of  sulfuric  acid  is  colorless.  Anti- 
pyrine.— A  mixture  of  100  mg.  of  aminopyrine, 
100  mg.  vanillin,  5  ml.  of  water  and  2  ml.  of 
sulfuric  acid,  heated  to  boiling,  has  no  more 
color  than  a  mixture  of  5  ml.  of  water,  2  ml.  of 
sulfuric  acid,  and  100  mg.  of  vanillin,  also  heated 
to  boiling.  N.F. 

Incompatibilities. — Aminopyrine  has  incom- 
patibilities very  similar  to  those  of  antipyrine.  It 
is  precipitated  by  many  alkaloidal  reagents  includ- 
ing iodine,  tannic  acid  and  Mayer's  reagent. 
Oxidizing  agents  produce  a  blue  to  violet  color; 
these  include  ferric  chloride,  silver  nitrate,  nitric 
acid,  nitrites,  iodine,  and  certain  enzymes.  Calo- 
mel and  mercury  bichloride  are  reduced.  Aspirin 
and  salol  are  discolored  and  become  moist  when 
mixed  with  it,  as  do  citric,  tartaric,  and  salicylic 
acids,  phenol,  and  chloral  hydrate.  Solutions  of 
aminopyrine  when  mixed  with  acacia  show  a  color 
change  from  violet,  through  yellow  to  brown. 
This  is  due  to  the  oxidase  of  acacia  and  may  be 
prevented  by  previously  heating  the  mucilage  on 
a  water  bath  for  30  minutes. 

Uses. — Aminopyrine  is  one  of  the  most  power- 
ful analgesics  of  the  "coal-tar  group"  but  because 
of  its  frequent  incrimination  in  cases  of  agranulo- 
cytosis its  use  in  this  country  has  been  largely 
discontinued.  Its  effect  on  the  threshold  for  pain, 
produced  by  radiant  heat  on  the  normal  skin,  was 
no  different  than  that  of  the  equivalent  dose  of 
acetanilid  or  acetylsalicylic  acid  (Wolff,  Hardy 
and   Goodell,  /.   Clin.  Inv.,   1941,   20,   63).   It 


will  relieve  neuralgic  headaches,  dysmenorrhea, 
rheumatism  and  similar  painful  conditions.  In 
rheumatic  fever  it  causes  diminution  of  fever 
and  relieves  the  joint  pain  as  effectively  as  do 
the  salicylates;  small  doses,  such  as  300  mg. 
three  to  six  times  daily,  are  adequate  (McEwen, 
Bull.  N.  Y.  Acad.  Med.,  1943,  19,  679).  A  few 
authors  believe  it  has  a  specific  curative  effect  on 
the  progress  of  the  disease.  (Bodenstab,  Deutsches 
Arch.  klin.  Med.,  1928,  159,  129).  Contrary  to 
some  reports  Borafski  and  Steigmann  (J.A.M.A., 
1933,  100,  1859)  found  its  effects  in  measles  to 
be  not  essentially  different  from  those  of  other 
coal-tar  antipyretics.  In  1932  Scherf  reported 
symptomatic  relief  in  diabetes  insipidus;  this  was 
confirmed  by  Kahn  (J.A.M.A.,  1933,  100,  1593). 
Large  doses  of  the  drug  intravenously  will  cause 
a  great  reduction  in  the  output  of  urine  for  6  or  8 
hours,  but  when  used  repeatedly  it  loses  its  anti- 
diuretic power.  In  healthy  persons  Weitzman 
(Ztschr.  klin.  Med.,  1940,  137,  429)  reported 
that  it  caused  increased  rather  than  decreased 
diuresis  following  the  ingestion  of  a  large  amount 
of  water. 

Toxicology. — The  most  dangerous  outcome 
from  the  use  of  aminopyrine  is  the  agranulocy- 
tosis which  develops  in  some  patients;  this  con- 
sists of  a  very  low  leukocyte  count  in  the  blood 
(as  low  as  a  few  hundred  per  cu.  mm.),  an  almost 
total  absence  of  granulocytes  (neutrophils),  a 
maturation  arrest  of  myeloblasts  in  the  bone  mar- 
row, fever,  malaise,  necrotic  ulcerations  of  the 
throat  and  other  mucous  membranes,  prostration 
and  death  in  as  high  as  70  per  cent  of  cases 
(Kracke  and  Parker,  J. A.M. A.,  1938,  111,  1255, 
and  FitzHugh,  ibid.,  p.  1643).  Since  agranulocy- 
tosis is  so  often  fatal,  and  since  other  effective 
analgesic  drugs  are  available,  the  use  of  amino- 
pyrine has  been  largely  discontinued,  [v] 

The  analgesic  dose  of  aminopyrine  is  from  130 
to  300  mg.  (approximately  2  to  5  grains) ;  a 
maximum  single  dose  of  600  mg.  and  maximum 
total  doses  of  1  to  3  Gm.  in  a  period  of  24  hours 
are  recorded,  which  latter  dose  is  hardly  to  be 
considered  safe. 

Storage. — Preserve  "in  well-closed,  light- 
resistant  containers."  N.F. 


AMINOPYRINE  ELIXIR.  N.F. 

Amidopyrine  Elixir,  [Elixir  Aminopyrinae] 

"Aminopyrine  Elixir  contains,  in  each  100  ml., 
not  less  than  3.7  Gm.  and  not  more  than  4.3  Gm. 
of  C13H17N3O."  N.F. 

Dissolve  40  Gm.  of  aminopyrine  in  200  ml.  of 
alcohol,  add  3  ml.  of  compound  orange  spirit,  10 
ml.  of  compound  amaranth  solution,  60  ml.  of 
glycerin,  400  ml.  of  syrup,  and  enough  purified 
water  to  make  the  product  measure  1000  ml.  Mix 
well  and  filter,  if  necessary,  to  produce  a  clear 
liquid.  N.F. 

Assay. — A  sample  of  5  ml.  of  elixir  is  alka- 
linized  with  ammonia  and  the  aminopyrine  ex- 
tracted with  successive  portions  of  chloroform. 
After  washing  the  chloroform  solution  with  water, 
the  former  is  filtered  into  a  tared  beaker,  the 
solvent  is  evaporated  and  the  residue  of  amino- 


70 


Aminopyrine    Elixir 


Part   I 


pyrine  dried  at  60°  for  2  hours,  cooled,  and 
weighed.  N.F. 

Alcohol  Content. — From  17  to  20  per  cent, 
by  volume,  of  C2H5OH.  N.F. 

This  preparation  is  an  acceptable  dosage  form 
for  aminopyrine,  but  it  should  be  used  cautiously 
in  view  of  the  potential  harmful  effect  of  the 
active  ingredient.  The  N.F.  gives  the  usual  dose 
as  4  ml.  (approximately  1  fluidrachm).  which 
represents  about  160  mg.  (approximately  2y2 
grains)  of  aminopyrine. 

Storage. — Preserve  "in  tight  containers."  N.F. 

AMINOPYRINE  TABLETS.     X.F.  (LP.) 

Amidopyrine  Tablets,  [Tabellae  Aminopyrinae] 

"Aminopyrine  Tablets  contain  not  less  than  94 
per  cent  and  not  more  than  106  per  cent  of  the 
labeled  amount  of  C13H17N3O."  N.F.  The  LP. 
limits  are  93.0  and  107.0  per  cent,  respectively. 

I. P.  Tablets  of  Amidopyrine;    Compressi  Amidopyrini. 

Assay. — A  representative  sample  of  tablets, 
equivalent  to  1  Gm.  of  aminopyrine.  is  dissolved 
in  1  N  hydrochloric  acid.  After  filtering  to  re- 
move insoluble  matter  an  aliquot  portion  of  the 
filtrate  is  rendered  alkaline  with  ammonia  T.S. 
and  the  aminopyrine  extracted  with  chloroform. 
The  chloroform  is  evaporated  and  the  residue  of 
aminopyrine  dried  at  60°  for  2  hours,  cooled  and 
weighed.  N.F. 

Usual  Size. — 5  grains  (approximately  300 
mg.). 

AMINOSALICYLIC  ACID.  U.S.P.,  (LP.) 

Para-aminosalicylic  Acid,  PAS 


COOH 


"Aminosalicylic  Acid  contains  not  less  than 
98.5  per  cent  of  C7H7NO3.  calculated  on  the  dried 
basis."  U.S.P.  The  LP.  requires  not  less  than  97.0 
per  cent  of  the  active  component,  referred  to  the 
substance  as  it  is  found. 

"Caution. — Prepare  solutions  of  Aminosalicylic 
Acid  within  24  hours  of  administration.  Under  no 
circumstances  use  a  solution  if  its  color  is  darker 
than  that  of  a  freshly  prepared  solution."  U.S.P. 

LP.  Para-aminosalicylic  Acid;  Acidum  Para-amino- 
salicylicum.  Pamisyl  {Parke-Davis).  4-Aminosalicylic  Acid; 
4-Amino-2-hydroxybenzoic  Acid. 

This  tuberculostatic  agent  may  be  synthesized 
by  several  processes,  as  by  carboxylation  of  m- 
aminophenol,  reduction  of  />-nitrosalicylic  acid, 
or  by  a  4-step  synthesis  starting  with  4-nitro-2- 
aminotoluene  (J.A.Ph.A.,  1949,  38,  9).  Besides 
the  acid,  the  calcium  and  sodium  salts  are  official. 

Description. — "Aminosalicylic  Acid  is  a  white 
or  nearly  white,  bulky  powder,  darkening  on 
exposure  to  fight  and  air.  It  is  odorless  or  has  a 
slight  acetous  odor.  One  Gm.  of  Aminosalicylic 
Acid  dissolves  in  about  500  ml.  of  water  and  in 
about  21  ml.  of  alcohol.  It  is  slightly  soluble  in 
ether  and  practically  insoluble  in  benzene."  U.S.P. 

Standards  and  Tests. — Identification. — (1) 
.The  diacetyl  derivative  melts  at  about  191°.  (2) 


On  adding  ferric  chloride  T.S.  to  a  saturated  solu- 
tion a  violet  color  is  produced.  (3)  The  acid 
melts  rapidly,  with  evolution  of  carbon  dioxide, 
between  145°  and  150°.  pH  —  The  pH  of  a  satu- 
rated solution  is  between  3.0  and  3.7.  Water. — 
Not  over  0.5  per  cent,  when  determined  by  the 
Karl  Fischer  method.  Residue  on  ignition. — Not 
over  0.1  per  cent.  Clarity  and  color  of  solution. — 
1  Gm.  dissolves  in  10  ml.  of  1  in  10  sodium  bicar- 
bonate solution  to  give  a  clear  solution  which  has 
no  more  than  a  faint  yellow  color.  Chloride. — 
The  limit  is  140  parts  per  million.  Arsenic. — The 
limit  is  10  parts  per  million.  Heavy  metals. — The 
limit  is  30  parts  per  million,  m- Amino  phenol. — 
Not  over  0.2  per  cent.  U.S.P. 

Assay. — About  300  mg.  of  aminosalicylic  acid 
is  dissolved  in  glacial  acetic  acid,  after  which  cold 
water,  ice,  and  hydrochloric  acid  are  added  and 
the  solution  is  titrated  with  0.1  M  sodium  nitrite 
until  it  produces  with  starch  iodide  paste  a  blue 
color  immediately.  In  this  assay  the  amino  group 
is  quantitatively  diazotized.  with  one  molecule  of 
aminosalicylic  acid  reacting  with  one  molecule  of 
sodium  nitrite.  Each  ml.  of  0.1  M  sodium  nitrite 
represents  15.31  mg.  of  C7H7NO3.  U.S.P.  In  the 
LP.  assay  about  300  mg.  of  the  acid  is  dissolved 
in  5  ml.  of  acetone  and  titrated  with  0.1  A7  sodium 
hydroxide,  using  bromothymol  blue  as  indicator. 
Each  ml.  of  0.1  N  sodium  hvdroxide  represents 
15.31  mg.  of  C7H7NO3. 

Stability. — Oberweger  et  al.  {Quart.  J.  P., 
194S,  21,  292)  investigated  the  stability  of  both 
the  acid  and  its  sodium  salt.  Dry  aminosalicylic 
acid  evolves  carbon  dioxide  at  temperatures  above 
100°  C,  melting  during  the  decomposition;  the 
sodium  salt  is  quite  stable  even  when  heated  at 
150°  C.  for  an  hour  and  may  be  sterilized  in  the 
dry  state  by  this  procedure,  after  first  dehydrating 
the  dihydrate  at  100°  to  110°  for  1.5  hour's.  Aque- 
ous solutions  of  the  acid  are  relatively  unstable, 
particularly  at  elevated  temperatures;  the  acid 
decomposes  to  w-aminophenol.  with  liberation  of 
carbon  dioxide.  Explosions  due  to  the  accumulated 
pressure  of  the  gas  formed  in  acid  solutions  of 
aminosalicylic  acid  have  been  reported  (Bulletin 
of  the  American  Society  of  Hospital  Pharmacists, 
Jan. -Feb.,  1950,  page  21).  The  sodium  salt  is  con- 
siderably more  stable  in  aqueous  solution  and  can 
be  boiled  without  marked  decarboxylation;  steri- 
lization by  autoclaving  results  in  appreciable  de- 
composition (15  per  cent  in  a  1  to  5  solution 
according  to  Oberweger  et  al.).  Solutions  of  the 
sodium  salt  develop  a  yellow  to  brown  color; 
color  formation  may  be  delayed  if  not  avoided 
entirely  by  dissolving  0.1  per  cent  of  sodium 
metabisulfite  in  the  solution.  Solutions  of  the  so- 
dium salt  for  oral  use  may  be  prepared  from 
anhydrous  aminosalicylic  acid  by  the  reaction,  in 
water,  of  153  parts  of  the  acid  with  84  parts  of 
sodium  bicarbonate,  i.e.,  in  the  proportion  of  the 
molecular  weights  of  the  two  substances. 

Uses. — Aminosalicylic  acid  has  been  used  in 
the  treatment  of  human  tuberculosis  since  Leh- 
mann's  observation  (Lancet,  1946,  250,  15)  that 
it  possesses  bacteriostatic  activity  against  tubercle 
bacilli. 

Action. — The  acid  is  rapidly  absorbed  from 
the  gastrointestinal  tract  and  diffuses  generally 


Part  I 


Ammonia 


71 


throughout  the  tissues,  the  highest  concentrations 
being  found  in  the  kidney,  lung  and  liver;  it  is 
also  found  in  cerebrospinal  fluid.  While  a  concen- 
tration of  0.15  mg.  per  100  ml.  is  bacteriostatic 
when  tested  against  tubercle  bacilli,  in  vitro  (Leh- 
mann,  loc.  cit.),  the  blood  levels  when  thera- 
peutic doses  are  given  are  of  the  order  of  2  to  11 
mg.  per  100  ml.  and  even  higher.  Aminosalicylic 
acid  must  be  given  at  intervals  of  2.5  to  3  hours 
to  maintain  continuously  elevated  blood  levels. 
Almost  all  of  it  is  excreted  in  the  urine  within 
10  hours  (McClosky  et  al,  J.  Pharmacol.,  1948, 
92,  447;  Way  et  al,  ibid.,  1948,  93,  368;  Venka- 
taraman  et  al,  J.  Biol.  Chem.,  1948,  173,  641). 
The  acid  is  bacteriostatic  rather  than  bactericidal 
but  the  exact  metabolic  function  altered  to  inhibit 
growth  is  undetermined. 

Tuberculosis. — Bogen  (Am.  Rev.  Tuberc, 
1950,  61,  226),  in  an  extensively  annotated  re- 
view, reported  that  most  investigators  found  early 
marked  symptomatic  improvement,  with  less 
cough  and  sputum,  increased  appetite,  slowing  of 
pulse  and  respiration,  and  a  drop  in  temperature 
especially  in  fever  due  to  tuberculous  pneumonia 
or  pleurisy,  following  use  of  aminosalicylic  acid. 
When  used  alone,  however,  the  acid  has  proved 
to  be  less  effective  than  streptomycin  (Tempel, 
J.A.M.A.,  1952,  150,  1165).  Aminosalicylic  acid 
may  be  given  by  itself  in  the  treatment  of  infec- 
tions due  to  streptomycin-resistant  tubercle  ba- 
cilli (American  Trudeau  Society,  Am.  Rev. 
Tuberc,  1951,  63,  617).  Its  use  in  conjunction 
with  isonicotinic  acid  hydrazide  is  being  investi- 
gated (Trans.  12th  Conf.  Chemoth.  Tbc,  1953). 
Some  authorities  recommend  aminosalicylic  acid 
alone  during  the  long-range  preparation  of  pa- 
tients for  resectional  operation.  Others  use  it  for 
symptomatic  relief  of  protracted,  incurable  tuber- 
culosis. 

The  concomitant  administration  of  aminosali- 
cylic acid  and  streptomycin  markedly  delays  the 
emergence  of  streptomycin-resistant  strains  of 
tubercle  bacilli  and  thus  prolongs  the  therapeutic 
effect  of  the  antibiotic.  On  a  120-day  regimen  of 
12  Gm.  of  aminosalicylic  acid  daily  and  1  Gm.  of 
streptomycin  twice  a  week,  resistance  to  10  micro- 
grams per  ml.  of  the  latter  was  reduced  from  82 
per  cent  to  less  than  20  per  cent  (Report,  Council 
on  Pharm.  &  Chem.,  J.A.M.A.,  1951,  147,  253). 
This  significant  reduction  in  bacterial  resistance 
has  been  accomplished  without  any  sacrifice  in 
therapeutic  efficacy.  In  fact,  pulmonary,  miliary, 
meningeal,  and  other  forms  of  tuberculosis  have 
all  shown  clinical  improvement  on  the  combined 
regimen. 

Toxicology. — Gastrointestinal  disturbances, 
consisting  of  nausea,  vomiting,  and  diarrhea,  are 
rather  frequent  early  in  the  course  of  treatment 
but  may  subside  with  continued  therapy.  Reduc- 
tion in  gastrointestinal  irritation  has  been  re- 
ported to  be  obtained  by  use  of  enteric-coated 
tablets  or  granules,  by  dispersion  in  a  flavored 
effervescent  drink,  by  oral  or  intravenous  adminis- 
tration of  a  solution  of  the  sodium  salt  or  by 
oral  use  of  the  potassium  salt  in  solution.  Serious 
toxic  reactions  are  rare.  A  few  allergic  reactions, 
including  dermatitis  and  drug  fever,  have  been 
reported.  Muri   (Nor disk  Med.,   1952,  47,    141) 


reported  a  case  of  fatal  aminosalicylic  acid  intoxi- 
cation and  Steininger  et  al.  (Am.  Rev.  Tuberc, 
1954,  69,  451)  reported  a  fatal  allergic  reaction 
from  a  5.5-Gm.  dose  of  sodium  aminosalicylate. 
Several  reports  of  thyroid  enlargement  occurring 
during  therapy  with  aminosalicylic  acid  have  ap- 
peared (Brinkman  and  Coates,  ibid.,  1954,  69, 
458).  Purpura  and  a  mild  hypoprothrombinemia 
have  been  observed.  Patients  with  impaired  he- 
patic or  renal  function  should  be  given  aminosali- 
cylic acid  with  caution. 

Dose. — The  usual  dose  is  3  Gm.  (approxi- 
mately 45  grains)  4  times  daily  by  mouth,  with  a 
range  of  2  to  4  Gm.  The  maximum  safe  dose  is 
4  Gm.  and  the  total  dose  in  24  hours  should  not 
exceed  16  Gm.  To  minimize  the  gastrointestinal 
disturbances,  which  are  frequent,  the  dose  should 
be  administered  with  meals ;  simultaneous  use  of  5 
to  10  ml.  of  aluminum  hydroxide  gel  is  recom- 
mended. Enteric-coated  granules  are  used  to  mini- 
mize discomfort.  Most  patients  tolerate  the  so- 
dium salt  better  and  this  salt  is  used  for  parenteral 
administration.  The  calcium  salt  is  also  official. 

Storage. — Preserve  "in  tight,  light-resistant 
containers."  U.S.P. 

AMINOSALICYLIC  ACID  TABLETS. 

U.S.P. 

"Aminosalicylic  Acid  Tablets  contain  not  less 
than  95  per  cent  and  not  more  than  105  per  cent 
of  the  labeled  amount  of  C7H7NO3."  U.S.P. 

Usual  Size. — 500  mg. 

AMMONIA 

Fr.  Ammoniac   (gaz).   Ger.  Ammoniak;   Ammoniakgas. 

One  of  the  most  important  compounds  of  nitro- 
gen is  ammonia,  NH3,  a  transparent  and  colorless 
gas  possessing  an  acrid  taste  and  an  exceedingly 
pungent  odor.  From  its  alkaline  reaction  and 
gaseous  nature  it  was  called  the  volatile  alkali  by 
the  earlier  chemists.  Ammonia  is  the  simplest 
form  of  the  class  of  bodies  described  as  amines, 
and  is  the  prototype  of  nitrogenous  organic  bases, 
which  may  be  considered  as  substituted  ammonias. 
The  word  "ammonia"  originated  from  the  fact 
that  it  was  near  the  temple  of  the  Egyptian  deity 
Ammon  that  the  earliest  sal  ammoniac  was  found 
as  a  product  originating  from  camels'  urine.  Solu- 
tions of  ammonia  have  been  known  and  used 
from  very  early  cimes.  The  substance  itself  was 
first  recognized  by  Priestley,  who  heated  the  aque- 
ous solution  of  ammonia  and  collected  the  gas 
over  mercury.  Its  components  and  the  proportion 
in  which  they  are  combined  were  determined  by 
Berthollet  and  by  Austin. 

Ammonia,  either  as  such  or  in  the  form  of  am- 
monium salts,  is  found  in  small  quantities  in  the 
air  and  in  most  natural  waters;  it  is  a  constituent 
in  plant  and  animal  fluids  and  in  a  few  minerals. 
It  is  formed  during  the  decay  of  nitrogenous 
organic  materials  and  is  an  important  factor  in 
plant  nutrition. 

Ammonium  compounds  are  sometimes  found  in 
sufficient  quantity  to  afford  a  satisfactory  natural 
source.  Some  of  the  guano  deposits  in  South 
America  contain  a  considerable  proportion  of 
ammonium  carbonate  and  have  been  used  as  a 


71 


Ammonia 


Part  I 


source  of  ammonia.  Volcanic  areas  frequently 
contain  quantities  of  ammonium  chloride  and  sul- 
fate. However,  only  a  small  proportion  of  the 
commercial  supply  is  obtained  from  natural 
sources.  A  considerable  quantity  of  ammonia  is 
obtained  in  the  manufacture  of  illuminating  gas, 
power  gases,  or  coke  from  coal  and  in  the  pro- 
duction of  shale  oil  from  shale.  Some  ammonia  is 
obtained  from  the  destructive  distillation  of  bones 
and  other  animal  and  vegetable  wastes.  But  the 
most  important  commercial  source  of  ammonia 
today  is  that  of  the  synthesis  of  ammonia  from 
its  constituent  elements,  nitrogen  and  hydrogen. 
The  techniques  of  manufacture  vary  consider- 
ably, but  in  general  the  processes  consist  of  a  re- 
action between  three  volumes  of  hydrogen  and 
one  volume  of  nitrogen  at  pressures  between  100 
and  1000  atmospheres  and  at  temperatures  rang- 
ing from  400°  to  550°,  while  in  contact  with  a 
promoted  iron  catalyst.  Nitrogen  for  the  reaction 
may  be  obtained  by  the  distillation  of  liquid  air 
or  from  the  manufacture  of  producer  gas.  Hydro- 
gen may  be  derived  from  the  reaction  of  natural 
gas  with  steam  in  the  presence  of  a  nickel  catalyst, 
from  the  electrolysis  of  brine,  or  from  coke  and 
steam  by  way  of  the  water-gas  reaction.  The 
German  chemist  Haber  was  the  first  to  develop 
a  process  for  synthesis  of  ammonia  from  its  ele- 
ments as  a  result  of  which  the  method  is  gener- 
ally designated  as  the  Haber  synthetic  ammonia 
process.  Ammonia  may  also  be  obtained  from  the 
compounds  formed  by  fixation  of  atmospheric 
nitrogen;  thus  calcium  cyanamide  may  be  made 
to  vield  it  in  accordance  wath  the  following  reac- 
tion: CaNCN  +  3H20  ->  CaCOa  +  2NH3. 

Ammonia  has  a  specific  gravity  of  0.597 
(air  =1).  The  gas  may  be  liquefied  or  solidified; 
the  solid  melts  at  — 85°,  the  liquid  boils  at 
— 33.4°.  It  is  very  soluble  in  water,  a  portion 
combining  with  the  water  to  form  ammonium  hy- 
droxide. It  is  easily  liquefied  by  compression.  In 
the  latter  form  it  is  available  on  the  market  in 
cylinders.  It  combines  with  acids  to  form  salts 
containing  the  ammonium  ion,  NH4+,  which  was 
named  by  Berzelius.  Ammonium  ion  acts  in  many 
respects  in  a  manner  analogous  to  the  ions  of  the 
alkaline  metals. 

In  addition  to  ammonium  salts,  ammonia  forms 
an  interesting  series  of  addition  compounds  with 
many  metallic  salts.  For  instance,  the  familiar 
deep  blue  solution  obtained  when  aqueous  am- 
monia is  added  to  a  cupric  salt  contains  such  an 
addition  compound.  Among  the  salts  which  com- 
bine in  this  manner  with  ammonia  are  those  of 
silver,  zinc,  copper,  chromium,  nickel,  cobalt,  and 
the  platinum  metals.  Usually  two,  four,  or  six 
molecules  of  ammonia  are  bound  to  the  metallic 
ion.  These  compounds  were  extensively  investi- 
gated by  Werner;  they  are  known  as  metal-am- 
monia complexes,  Werner's  complexes,  or  ammines 
(not  amines,  which  are  organic  derivatives). 

The  largest  peace-time  use  of  ammonia  is  in 
the  manufacture  of  fertilizers;  indeed,  ammonia 
is  in  some  areas  applied  directly  to  the  soil  as  a 
fertilizer.  Ammonia  also  enters  into  the  manufac- 
ture of  many  chemicals  and  such  substances  as 
rubber,  plastics,  various  synthetic  textile  fibers, 
.  lacquers,  etc.  It  is  also  employed  as  a  refrigerant. 


In  the  steel  industry  it  is  used  to  harden  steel  by 
virtue  of  its  forming  a  nitride.  In  time  of  war 
ammonia  is  of  commanding  importance  because 
it  is  the  starting  point  for  the  manufacture  of 
almost  all  military  explosives. 

Physiological  Action. — Ammonia  is  an  irre- 
spirable  gas;  it  is  so  irritant  that  the  instant  it 
comes  in  contact  with  the  glottis  is  causes  imme- 
diate spasm  of  that  orific  and  inhibition  of  res- 
piration. Continued  exposure  to  high  concentra- 
tions, however,  may  be  sufficiently  irritating  to 
produce  pulmonary  edema.  Repeated  or  long- 
continued  exposure  to  low  concentrations  of  the 
gas  will  cause  chronic  pulmonary  irritation,  but 
less  than  250  parts  per  million  of  the  vapor  are 
probably  harmless.  Exposure  of  the  skin  to  the 
concentrated  gas  leads  to  vesicle  formation.  Its 
only  therapeutic  value  lies  in  its  local  irritant 
effects,  for  it  cannot  circulate  in  the  blood  stream, 
being  there  converted  into  ammonium  salts. 
Remedial  effects  of  ammonia  water  or  aromatic 
ammonia  spirit  are  due  to  the  evolution  of  am- 
monia gas  which  irritates  the  nasal  mucous  mem- 
brane, and  reflexly  stimulates  the  respiratory  and 
vasomotor  centers. 

For  description  of  ammonia  poisoning,  see 
under  Diluted  Ammonia  Solution.  For  account  of 
physiologic  properties  of  ammonium  ion  see  under 
Ammonium  Carbonate. 

DILUTED  AMMONIA  SOLUTION. 
U.S.P.  (B.P.) 

Ammonia  Water,  Diluted  Ammonium  Hydroxide 
Solution,  Liquor  Ammonia;  Dilutus 

"Diluted  Ammonia  Solution  is  a  solution  of 
NH3  containing,  in  each  100  ml.,  not  less  than 

9  Gm.  and  not  more  than  10  Gm.  of  NH3.  Upon 
exposure  to  air  it  loses  ammonia  rapidly."  U.S.P. 
The  B.P.  Dilute  Solution  of  Ammonia  contains 

10  per  cent  w/w  (limits,  9.5  to  10.5)  of  NH3. 

B.P.  Dilute  Solution  of  Ammonia.  Solution  of  Ammonia. 
Liquor  Ammonii  Hydroxidi ;  Liquor  Ammonii  Caustici 
(Ger.);  Ammonia  Caustica  Diluta.  Fr.  Ammoniaque  offi- 
cinale diluee;  Solution  aqueuse,  au  dixieme.de  gaz  am- 
moniac. Ger.  Ammoniakfliissigkeit.  It.  Soluzione  di  am- 
moniaca.  Sp.  Solution  de  Amoniaco  Diluida. 

Diluted  ammonia  solution  may  be  prepared  by 
diluting  398  ml.  of  strong  ammonia  solution  with 
sufficient  purified  water  to  make  1000  ml.  U.S.P. 

Description. — "Diluted  Ammonia  Solution  is 
a  colorless,  transparent  liquid,  having  a  very 
pungent,  characteristic  odor.  It  is  alkaline  to 
litmus.  Its  specific  gravity  is  about  0.96."  U.S.P. 

Standards  and  Tests. — Identification. — 
Dense,  white  fumes  are  produced  when  a  glass  rod 
wet  with  hydrochloric  acid  is  held  near  diluted 
ammonia  solution.  Non-volatile  substances. — Not 
over  2  mg.  of  residue  is  obtained  on  evaporating 
10  ml.  of  diluted  ammonia  solution  and  drying  at 
105°  for  1  hour.  Heavy  metals. — The  limit  is  5 
parts  per  million.  Readily  oxidizable  substances. 
— The  pink  color  of  a  mixture  of  10  ml.  of  diluted 
ammonia  solution  with  a  slight  excess  of  diluted 
sulfuric  acid  and  0.1  ml.  of  0.1  N  potassium  per- 
manganate does  not  completely  disappear  in  10 
minutes.  U.S.P. 

The  B.P.  provides  a  test  for  limit  of  tarry  mat- 
ter in  which  6  Gm.  of  powdered  citric  acid  is  dis- 


Part  I 


Ammonia   Solution,   Strong  73 


solved  in  15  ml.  of  dilute  solution  of  ammonia: 
no  tarry  odor  is  perceptible.  The  arsenic  and 
lead  limits  are  0.1  and  0.3  part  per  million, 
respectively. 

Assay. — A  portion  of  5  ml.  of  diluted  ammonia 
solution  is  mixed  with  water  and  titrated  with  1  N 
sulfuric  acid,  using  methyl  red  T.S.  as  indicator. 
Each  ml.  of  1  N  sulfuric  acid  represents  17.03  mg. 
of  NH3.  U.S.P.  In  the  B.P.  assay  the  ammonia 
solution  is  weighed  into  a  measured  excess  of  1  N 
hydrochloric  acid;  the  excess  of  acid  is  titrated 
with  1  N  sodium  hydroxide  using  methyl  red  as 
indicator. 

Composition. — Water  is  capable  of  dissolving 
large  amounts  of  ammonia;  one  volume  of  water 
at  0°  and  1  atmosphere  dissolves  1298  volumes 
of  the  gas,  and  at  20°  it  dissolves  710  volumes. 
To  a  large  extent  the  ammonia  dissolves  as  such; 
a  portion  of  it  combines  chemically  with  water  to 
form  the  weak  base,  ammonium  hydroxide,  which 
dissociates  slightly  into  ammonium  and  hydroxyl 
ions.  Some  hydrates  of  NH3  are  also  present. 

Incompatibilities. — Ammonium  hydroxide  re- 
acts with  acids  to  form  the  corresponding  am- 
monium salts  and  with  many  metals  forms  a  pre- 
cipitate. Alkaloids  are  precipitated  from  solutions 
of  their  salts.  Free  iodine  may  form  nitrogen 
iodide  which  is  explosive  when  dry. 

Uses. — When  brought  into  contact  with  living 
tissue,  ammonia  solution  acts  as  a  stimulant,  irri- 
tant, or  caustic  according  to  the  concentration  of 
the  solution.  The  official  diluted  ammonia  solu- 
tion, if  applied  for  a  short  time  to  the  skin,  pro- 
duces burning  pain  and  redness;  if  contact  is  pro- 
longed it  is  capable  of  destroying  the  whole 
dermal  tissue.  When  injected  into  the  circulation, 
diluted  ammonia  solution  produces  the  character- 
istic effects  of  ammonium  salts  but  for  reasons 
pointed  out  elsewhere  (see  under  Ammonium 
Carbonate)  it  cannot  be  absorbed  from  the  stom- 
ach in  sufficient  quantity  to  exercise  any  direct 
influence  upon  the  general  system.  It  is  widely 
used  for  sudden  syncope  of  nervous  origin.  By 
the  mouth,  the  effects  are  due  to  reflex  stimula- 
tion of  the  vasomotor  center  from  irritation  of 
the  gastric  mucous  membrane.  Still  more  marked 
action  of  the  same  nature  follows  smelling  of 
ammonia  vapor,  as  from  ammonia  water  (see  also 
under  Ammonia).  If  injected  hypodermically,  the 
resulting  pain  is  a  powerful  reflex  stimulant  to 
circulation  and  respiration.  It  may  cause  necrosis 
at  the  injection  site.  Although  it  is  an  alkali,  it  is 
too  irritant  to  be  useful  as  a  gastric  antacid. 

Ammonia  water  is  used  as  an  ingredient  of 
stimulating  liniments,  especially  when  combined 
with  olive  or  other  oil.  Under  the  title  Ammonia 
Liniment  the  N.F.  IX  recognized  a  preparation 
made  by  mixing  10  ml.  of  oleic  acid  with  740  ml. 
of  sesame  oil,  adding  250  ml.  of  diluted  ammonia 
solution  and  agitating  until  a  uniform  mixture 
resulted,  [v] 

Toxicology. — The  symptoms  of  poisoning  by 
ammonia  are  solely  those  of  local  irritation :  pain 
in  the  mouth,  throat,  and  epigastrium;  vomiting 
and  collapse  from  the  severity  of  the  gastritis. 
Conjunctivitis  is  common.  The  conjunctiva  should 
be  rinsed  with  water  or  isotonic  sodium  chloride 
solution.  In  some  cases  the  irritation  of  the  throat 


is  so  severe  as  to  produce  an  acute  edema  of  the 
glottis  which  may  mechanically  obstruct  respira- 
tion and  cause  rapid  death  from  asphyxia.  In  the 
treatment  of  the  condition,  passage  of  the  stom- 
ach tube  or  the  use  of  emetics  is  contraindicated 
because  of  the  danger  of  perforation.  Diluted 
acetic  acid  in  the  form  of  vinegar  may  be  used 
as  an  antidote;  olive  oil  or  some  other  fatty  sub- 
stance is  useful  not  only  because  it  combines 
with  the  caustic  alkali  to  form  a  comparatively 
nonirritant  soap,  but  also  by  virtue  of  its  local 
soothing  action  upon  the  inflamed  mucosa.  Mor- 
phine sulfate  hypodermically  may  be  used  safely 
to  relieve  pain.  In  case  of  edema  of  the  larynx, 
tracheotomy  is  indicated;  it  should  be  realized 
that  this  condition  may  not  develop  for  an  hour 
or  two  after  the  ingestion  of  the  poison  and  the 
physician  should  remain  ready  for  immediate 
operation  if  necessary.  The  subsequent  treatment 
is  purely  symptomatic. 

Dose,  from  0.6  to  2  ml.  (approximately  10  to 
30  minims),  largely  diluted. 

Storage. — Preserve  "in  tight  containers,  pref- 
erably at  a  temperature  not  above  30°."  U.S.P. 

Off.  Prep. — Aromatic  Ammonia  Spirit,  U.S.P.; 
Bismuth  Magma;  Senega  Syrup;  Washed  Sulfur, 
N.F. 

STRONG  AMMONIA  SOLUTION. 
U.S.P.  (B.P.) 

Stronger  Ammonia  Water,  Stronger  Ammonium 
Hydroxide  Solution,  Liquor  Ammonias  Fortis 

"Strong  Ammonia  Solution  is  a  solution  of 
NH3,  containing  not  less  than  27  per  cent  and  not 
more  than  30  per  cent  of  NH3.  Upon  exposure  to 
air  it  loses  ammonia  rapidly.  Caution. — Great  care 
should  be  used  in  handling  Strong  Ammonia  Solu- 
tion because  of  the  caustic  and  irritating  proper- 
ties of  its  vapor.  Before  the  container  is  opened  it 
should  be  well  cooled  and  the  closure  covered 
with  a  towel  before  removal.  Strong  Ammonia 
Solution  must  never  be  tasted  nor  its  vapor  in- 
haled." U.S.P. 

The  B.P.  Strong  Solution  of  Ammonia  is  more 
concentrated  than  the  U.S.P.  solution.  It  contains 
32.5  per  cent  w/w  of  NH3  (limits  31.5  to  33.5). 

B.P.  Strong  Solution  of  Ammonia.  Sp.  Solution  de 
Amoniaco  Fuerte. 

Strong  ammonia  solution  may  be  obtained  by 
dissolving  ammonia  gas  in  water.  The  solution  is  a 
complex  preparation,  containing  NH3,  hydrates 
of  the  latter,  some  NH4OH  and  small  amounts 
of  NH4+  and  OH-. 

Description. — "Strong  Solution  of  Ammonia 
is  a  colorless,  transparent  liquid,  having  an  ex- 
ceedingly pungent,  characteristic  odor.  It  is 
strongly  alkaline  to  litmus.  Its  specific  gravity  is 
about  0.90."  U.S.P. 

Standards  and  Tests. — Strong  ammonia  solu- 
tion, diluted  with  one  and  one-half  volumes  of 
water,  meets  the  requirements  of  the  tests  for 
non-volatile  substances,  heavy  metals,  and  readily 
oxidizable  substances  under  Diluted  Ammonia  So- 
lution. U.S.P.  The  B.P.  has  a  test  for  limit  of 
tarry  matter  (see  under  Diluted  Ammonia  Solu- 
tion), and  sets  the  limits  of  arsenic  and  lead  at 
0.4  and  1  part  per  million,  respectively. 


74  Ammonia   Solution,   Strong 


Part   I 


Assay. — About  2  ml.  of  strong  ammonia  solu- 
tion is  weighed  accurately  in  a  glass-stoppered 
flask  containing  water  and  titrated  with  1  N  sul- 
furic acid,  using  methyl  red  T.S.  as  indicator. 
Each  ml.  of  1  AT  sulfuric  acid  represents  17.03  mg. 
of  NH3.  U.S.P.  In  the  B.P.  assay  the  ammonia 
solution  is  weighed  in  a  flask  containing  a  meas- 
ured excess  of  1  N  hydrochloric  acid;  the  excess 
of  acid  is  titrated  with  1  N  sodium  hydroxide. 

Great  care  should  be  exercised  in  opening 
bottles  containing  strong  ammonia  solution.  It  is 
safer,  if  the  solution  has  been  kept  in  a  warm 
room,  to  cool  it  with  ice  before  attempting  to 
withdraw  the  stopper,  as  the  liberated  gas,  when 
warm,  frequently  is  forced  out  under  considerable 
pressure,  and  accidents  which  have  resulted  in 
injury  to  the  sight  of  the  operator  are  recorded. 

Uses. — Strong  ammonia  solution  is  too  potent 
for  medicinal  use  in  its  original  concentration  but 
provides  a  convenient  solution  for  dilution  to  the 
strength  of  ordinary  ammonia  water.  Sufficiently 
diluted  with  camphor  and  rosemary  spirits,  it  was 
formerly  employed  as  an  irritant  lotion  for 
alopecia.  The  inadvertent  inhalation  of  the  gas 
escaping  from  strong  ammonia  solution  may  cause 
inflammation  of  the  upper  respiratory  tract.  The 
best  antidote,  under  these  circumstances,  is  the 
inhalation  of  vapors  of  vinegar  or  acetic  acid. 
(For  toxicology,  see  under  Diluted  Ammonia 
Solution.)  E 

Dose,  0.2  to  0.4  ml.  (approximately  3  to  6 
minims),  largely  diluted. 

Storage. — Preserve  "in  tight  containers,  pref- 
erably at  a  temperature  not  above  25°."  U.S.P. 

Off.  Prep.— Diluted  Ammonia  Solution,  U.S.P., 
B.P.;  Ammoniacal  Silver  Nitrate  Solution,  N.F.; 
Ammoniated  Liniment  of  Camphor;  Aromatic 
Spirit  of  Ammonia,  B.P. 

AROMATIC  AMMONIA  SPIRIT. 
U.S.P.  (B.P.) 

[Spiritus  Ammoniac  Aromaticus] 

"Aromatic  Ammonia  Spirit  contains,  in  each 
100  ml.,  not  less  than  1.7  Gm.  and  not  more  than 
2.1  Gm.  of  total  NH3,  and  ammonium  carbonate, 
corresponding  to  not  less  than  3.5  Gm.  and  not 
more  than  4.5  Gm.  of  (NH^COa."  U.S.P. 

The  B.P.  Aromatic  Spirit  of  Ammonia  con- 
tains 1.185  per  cent  w/v  of  free  ammonia  (limits, 
1.12  to  1.25),  calculated  as  NH3,  and  3.0  per  cent 
w/v  of  ammonium  carbonate  (limits,  2.76  to 
3.24),  calculated  as  (NH4)2C03. 

B.P.  Aromatic  Spirit  of  Ammonia.  "Aromatics";  Spirit 
of  Sal  Volatile.  Sp.  Espiritu  Aromatico  de  Amoniaco. 

Dissolve  34  Gm.  of  translucent  ammonium  car- 
bonate in  90  ml.  of  diluted  ammonia  solution  and 
140  ml.  of  purified  water  by  gentle  agitation,  and 
allow  the  solution  to  stand  for  12  hours.  Dissolve 
10  ml.  of  lemon  oil,  1  ml.  of  lavender  oil  and  1  ml. 
of  myristica  oil  in  700  ml.  of  alcohol  contained 
in  a  graduated  bottle  or  cylinder,  and  add  gradu- 
ally the  ammonium  carbonate  solution  along  with 
enough  purified  water  to  make  1000  ml.  Set  the 
mixture  aside  in  a  cool  place  for  24  hours,  agi- 
tating it  occasionally,  and  then  filter,  using  a 
covered  funnel.  US.P. 

The  B.P.  prepares  aromatic  spirit  of  ammonia 


by  distilling  a  mixture  of  alcohol,  water,  lemon 
oil  and  nutmeg  oil,  collecting  two  portions  of 
distillate,  the  first  and  larger  portion  containing 
most  of  the  alcohol  and  oils,  and  the  second  por- 
tion representing  largely  water  saturated  with 
oils;  the  ammonium  bicarbonate  and  stronger 
ammonia  water  are  dissolved  in  the  aqueous  frac- 
tion of  the  distillate  and  then  mixed  with  the 
distillate  representing  the  hydroalcoholic  solution 
of  the  oils.  The  B.P.  preparation  is  slightly 
stronger  in  ammonia  water  and  slightly  weaker 
in  ammonium  carbonate. 

Under  ammonium  carbonate  it  was  pointed  out 
that  this  substance  is  a  mixture  of  ammonium 
carbamate  and  ammonium  bicarbonate.  In  the 
hydroalcoholic  medium  of  aromatic  ammonia 
spirit  the  carbamate  dissolves  completely  and  is 
converted  by  water  to  carbonate;  the  bicarbonate, 
however,  because  of  its  insolubility  in  alcohol, 
would  be  largely  precipitated  if  ammonia  were  not 
included  to  convert  it  to  carbonate.  This  need  for 
ammonia  is  all  the  more  necessary  because  am- 
monium carbonate  which  has  been  exposed  to  the 
air  for  a  long  time  will  have  been  in  considerable 
part  converted  to  ammonium  bicarbonate  by  loss 
of  ammonia;  in  the  presence  of  ammonia  the 
bicarbonate  is  converted  again  to  carbonate.  But 
even  with  the  inclusion  of  ammonia  it  is  impera- 
tive that  translucent  pieces  af  ammonium  car- 
bonate be  used,  for  the  amount  of  ammonia  may 
be  inadequate  to  convert  a  large  amount  of  bi- 
carbonate to  carbonate,  with  the  result  that  a 
part  of  the  bicarbonate  remains  insoluble.  The 
U.S.P.  allows  12  hours  for  the  reaction  between 
ammonia  and  the  components  of  ammonium  car- 
bonate to  become  completed.  If  directions  are 
followed  in  every  detail,  the  precipitation  (of 
ammonium  bicarbonate)  sometimes  observed  will 
not  occur. 

Description. — "Aromatic  Ammonia  Spirit  is  a 
nearly  colorless  liquid  when  recently  prepared,  but 
gradually  acquires  a  yellow  color  on  standing.  It 
has  the  taste  of  ammonia,  has  an  aromatic  and 
pungent  odor,  and  is  affected  by  light.  Its  specific 
gravity  is  about  0.90."  US.P. 

The  yellow  color  acquired  by  the  spirit,  on 
standing,  is  due  either  to  alteration  of  the  volatile 
oils,  or  to  a  reaction  of  aldehydes  in  alcohol  in 
the  presence  of  alkali.  Despite  the  change  in  color, 
the  spirit  retains  its  therapeutic  activity. 

Assay. — For  total  ammonia. — A  10-ml.  por- 
tion of  spirit  is  diluted  with  water,  mixed  with 
30  ml.  of  0.5  N  sulfuric  acid,  and  the  mixture 
boiled  until  a  clear  solution  results,  after  which 
the  excess  of  acid  is  titrated  with  0.5  N  sodium 
hydroxide,  using  methyl  red  T.S.  as  indicator. 
Each  ml.  of  0.5  N  acid  represents  8.516  mg.  of 
XH3.  For  ammonium  carbonate. — A  second  10-ml. 
portion  of  spirit  is  mixed  with  30  ml.  of  0.5  N 
sodium  hydroxide,  the  mixture  boiled  until  the 
ammonia  is  expelled  and  an  amount  of  sodium 
carbonate  equivalent  to  the  ammonium  carbonate 
originally  present  is  formed,  and  the  solution 
neutralized  with  0.5  N  sulfuric  acid,  first  to 
phenolphthalein  T.S.,  and  then  to  methyl  orange 
T.S.  Each  ml.  of  0.5  N  acid  consumed  in  the 
presence  of  methyl  orange  represents  48.05  mg. 
of  (NH4)2C03.  This  equivalent  is  based  on  the 


Part  I 


Ammonium   Acetate,  Strong   Solution   of  75 


fact  that  at  the  phenolphthalein  endpoint  the 
carbonate  has  been  converted  to  bicarbonate,  and 
that  it  is  only  the  latter  which  is  neutralized  in 
the  presence  of  methyl  orange. 

The  B.P.  assays  for  free  ammonia  by  essen- 
tially the  same  method  that  the  U.S. P.  employs 
for  total  ammonia,  except  that  from  the  amount 
of  acid  required  to  neutralize  both  free  and  com- 
bined ammonia  is  subtracted  the  amount  equiva- 
lent to  the  ammonium  carbonate  present.  In  the 
assay  for  ammonium  carbonate  the  following 
steps  are  performed:  the  sample  of  spirit  is 
treated  with  a  solution  of  barium  chloride  to  pre- 
cipitate barium  carbonate  and  form  an  equivalent 
amount  of  ammonium  chloride;  simultaneously  a 
measured  excess  of  1  ^  sodium  hydroxide  is 
added,  which  reacts  with  the  ammonium  chloride 
to  form  sodium  chloride  and  ammonia;  the  am- 
monia from  this  reaction,  as  well  as  that  present 
in  the  spirit  initially,  is  reacted  with  formaldehyde 
to  convert  it  to  methenamine;  finally,  the  excess 
of  the  sodium  hydroxide  solution  is  titrated  with 
1  N  hydrochloric  acid,  using  thymol  blue  indi- 
cator. Each  ml.  of  1  N  sodium  hydroxide  repre- 
sents 48.05  mg.  of  (NEU)2C03. 

Alcohol  Content. — From  62  to  68  per  cent, 
by  volume,  of  C2H5OH.  U.S.P. 

Uses. — Aromatic  ammonia  spirit  is  used  as  a 
mild  stimulant  in  syncope  and  other  forms  of 
circulatory  weakness.  Its  action  is  purely  reflex, 
resulting  from  irritation  of  the  mucous  membrane 
of  the  alimentary  tract.  Although  ammonia  is  a 
stimulant  to  the  circulation  it  can  act  only  when 
injected  hypodermically.  Aromatic  ammonia  spirit 
has  been  used  for  "sick  headache."  H 

The  usual  dose  is  2  ml.  (approximately  30 
minims),  well  diluted  with  water.  The  maximum 
safe  dose  is  usually  4  ml.  and  the  total  dose  in  24 
hours  should  seldom  exceed  10  ml. 

Storage. — Preserve  "in  tight,  light-resistant 
containers,  preferably  at  a  temperature  not  above 
30°."  U.S.P. 

AMMONIUM  ACETATE  SOLUTION. 
N.F.  (B.P.) 

[Liquor  Ammonii  Acetatis] 

"Ammonium  Acetate  Solution  contains,  in  each 
100  ml.,  not  less  than  6.5  Gm.  and  not  more 
than  7.5  Gm.  of  CH3COONH4,  with  small 
amounts  of  acetic  and  carbonic  acids.  Note. — 
Dispense  only  recently  prepared  Ammonium 
Acetate  Solution."  N.F.  The  B.P.  limits  of  am- 
monium acetate  for  this  solution  are  from  6.9  to 
7.5  per  cent  w/v. 

B.P.  Dilute  Solution  of  Ammonium  Acetate,  Liquor 
Ammonii  Acetatis  Dilutus.  Spirit  of  Mindererus.  Am- 
monium Aceticum  Solutum;  Ammonii  Acetas  Liquidus; 
Liquor  Ammonii  Acetici.  Fr.  Acetate  d'ammonium  dis- 
sous;  Solution  officinale  d'acetate  d'ammonium;  Acetate 
d'ammonium  liquide.  Ger.  Ammoniumacetatlosung.  It. 
Soluzione  di  acetato  di  ammonio.  Sp.  Acetato  de  amonio 
liquido;    Acetato   amonico   liquido;    Espiritu   de    minderero. 

Dissolve  50  Gm.  of  ammonium  carbonate,  in 
hard,  translucent  pieces,  in  sufficient  diluted 
acetic  acid  to  make  1000  ml.  of  solution.  Avoid 
strong  agitation  of  the  solution  during  its  prepara- 
tion. The  solution  may  also  be  prepared  by  mix- 
ing equal  volumes  of  the  following  solutions: 
Solution  No.  1. — Dissolve  100  Gm.  of  ammonium 


carbonate,  in  hard,  translucent  pieces,  in  suffi- 
cient purified  water  to  make  1000  ml.  Solution 
No.  2. — Mix  320  ml.  of  acetic  acid  with  sufficient 
purified  water  to  make  1000  ml.  of  solution.  N.F. 

The  B.P.  equivalent  of  this  preparation  is  made 
by  diluting  the  stronger  solution  (q.v.)  with  seven 
parts  of  distilled  water. 

The  palatability  and  compatibility  of  this  solu- 
tion are  enhanced  by  having  in  it  a  slight  excess 
of  acetic  acid  and  carbon  dioxide;  it  is,  there- 
fore, important  that  the  ammonium  carbonate  be 
not  decomposed  and  that  the  acetic  acid  be  of 
specified  strength.  Particularly  to  insure  having 
carbon  dioxide  in  the  solution  as  it  is  dispensed,  it 
should  be  prepared  as  required  for  immediate  use. 

Description. — "Ammonium  Acetate  Solution 
is  a  clear,  colorless  liquid,  free  from  empyreu- 
matic  odor.  It  has  a  mildly  salty,  acid  taste,  and 
an  acid  reaction  to  litmus."  N.F. 

Standards  and  Tests. — Identification. — Am- 
monium acetate  solution  responds  to  tests  for 
ammonium  and  for  acetate.  Residue  on  ignition. — 
The  residue  from  20  ml.  of  solution  does  not 
exceed  3  mg.  N.F. 

Assay. — A  portion  of  25  ml.  is  diluted  with 
water,  made  alkaline  with  sodium  hydroxide  T.S. 
and  the  ammonia  distilled  out  of  the  mixture  into 
50  ml.  of  1  N  sulfuric  acid;  the  excess  acid  is 
titrated  with  1  N  sodium  hydroxide  using  methyl 
red  T.S.  as  indicator.  Each  ml.  of  1  A7  sulfuric 
acid  represents  77.08  mg.  of  CH3COONH4.  N.F. 
The  B.P.  assay  is  explained  under  Strong  Solution 
of  Ammonium  Acetate. 

Uses. — Ammonium  acetate  solution  is  used  as 
a  saline  diaphoretic  and  diuretic,  especially  in 
febrile  conditions,  [Yl 

Dose,  from  15  to  30  ml.  (approximately  Yi  to  1 
fluidounce)  every  two  or  three  hours,  mixed  with 
water  and  sweetened. 

Storage. — Preserve  "in  tight  containers."  N.F. 

Off.  Prep. — Iron  and  Ammonium  Acetate  So- 
lution, N.F. 

STRONG  SOLUTION  OF  AMMONIUM 
ACETATE.     B.P. 

Liquor  Ammonii  Acetatis  Fortis 

This  solution  contains  about  57.5  per  cent 
w/v  of  ammonium  acetate  (limits,  55.0  to  60.0 
per  cent)  and  is  prepared  by  the  interaction  in  an 
aqueous  solution  of  glacial  acetic  acid,  ammonium 
bicarbonate  and  sufficient  strong  ammonia  solu- 
tion to  make  the  pH  of  the  solution,  when  a 
portion  of  it  is  diluted  with  10  volumes  of  water, 
between  7  and  8  (the  test  being  based  on  the 
production  of  a  full  blue  color  with  bromothymol 
blue  solution  and  a  full  yellow  color  with  thymol 
blue  solution). 

Description  and  Standards. — The  solution 
is  described  as  a  thin  syrupy  liquid  having  an  odor 
of  ammonia  as  well  as  of  acetic  acid;  the  weight 
per  ml.,  at  20°,  is  about  1.094  Gm.  Arsenic  and 
lead  limits  of  4  p.p.m.  and  5  p.p.m.,  respectively, 
are  prescribed. 

Assay. — A  sample  of  5  ml.  of  solution  is 
diluted  with  water,  formaldehyde  neutralized  to 
phenolphthalein  is  added,  and  the  solution  titrated 
with  1  N  sodium  hydroxide,  using  phenolphthalein 


76  Ammonium   Acetate,  Strong   Solution   of 


Part  I 


solution  as  indicator.  Each  ml.  of  I  N  sodium  hy- 
droxide represents  77.08  mg.  of  ammonium  ace- 
tate. This  assay  is  based  on  the  fact  that  hydroly- 
sis of  ammonium  acetate  to  ammonia  and  acetic 
acid  may  be  made  complete  by  having  formalde- 
hyde present  to  react  with  ammonia,  forming 
methenamine,  and  leaving  acetic  acid  to  be  ti- 
trated with  alkalki. 

Dose,  from  1  to  4  ml.  (approximately  15  to  60 
minims). 

Storage. — Preserve  in  a  bottle  made  of  lead- 
free  glass.  B.P. 

Off.  Prep. — Dilute  Solution  of  Ammonium 
Acetate,  B.P. 

AMMONIUM   BICARBONATE.     B.P. 

Ammonii  Bicarbonas 

Ammonium  Bicarbonate  contains  not  less  than 
98.0  per  cent  of  NH4HCO3.  B.P. 

Fr.  Carbonate  acide  d'ammonium.  Gcr  Ammoniumbicar- 
bonat;  Doppeltkohlensaures  Ammonium.  Sp.  Bicarbonato 
amonico. 

Ammonium  bicarbonate  may  be  prepared  by  a 
number  of  methods.  One  of  these  consists  in  sub- 
liming so-called  "ammonium  carbonate"  (really 
a  mixture  of  ammonium  bicarbonate  and  am- 
monium carbamate;  see  Ammonium  Carbonate) 
in  the  presence  of  a  little  water,  a  white  fibrous 
mass  of  ammonium  bicarbonate,  somewhat  con- 
taminated with  the  carbamate,  being  obtained.  By 
washing  the  mass  with  alcohol  the  carbamate  is 
dissolved  while  the  bicarbonate  remains  insoluble. 
Ammonium  bicarbonate  may  also  be  prepared  by 
passing  carbon  dioxide  into  an  aqueous  solution 
of  ammonia  or  by  treating  "ammonium  carbonate'' 
with  alcohol  in  order  to  remove  the  carbamate. 

Description  and  Standards. — Ammonium 
bicarbonate  occurs  as  colorless  crystals  or  a  white 
crystalline  powder.  It  is  slightly  hygroscopic,  dis- 
solves in  5  parts  of  water  (at  20°)  but  is  in- 
soluble in  alcohol.  It  volatilizes  slowly  at  room 
temperatures.  At  60°  it  rapidly  dissociates  into 
ammonia,  carbon  dioxide  and  water.  It  gives  the 
characteristic  reactions  of  the  ammonium  salts 
and  of  the  bicarbonates. 

Pure  ammonium  bicarbonate  does  not  possess 
the  irritant  odor  of  ammonia,  but  because  the 
commercial  preparations  often  contain  traces  of 
carbamate,  ammonia  is  produced  in  consequence 
of  the  dissociation  of  the  latter.  According  to 
Whittet  (Pkarm.  J.,  1949,  162,  24),  solutions  of 
ammonium  bicarbonate  are  stable  for  at  least  6 
months  if  stored  in  glass-stoppered  bottles;  ex- 
posed to  air  the  solutions  steadily  decompose  be- 
cause of  the  release  of  ammonia  and  carbon 
dioxide. 

The  B.P.  includes  tests  for  limits  of  tarry  mat- 
ter, chlorides,  sulfates,  arsenic,  lead  and  iron.  It 
may  be  assayed  by  dissolving  2  Gm.  in  40  ml.  of 
1  N  hydrochloric  acid,  boiling  the  solution  to 
expel  carbon  dioxide,  cooling,  and  finally  titrating 
the  excess  of  acid  with  1  N  sodium  hydroxide 
solution,  using  methyl  red  as  the  indicator. 

Uses. — This  drug  is  very  similar  in  its  thera- 
peutic range  to  the  so-called  ammonium  carbonate 
which  is.  as  a  matter  of  fact,  largely  composed 
of  the  bicarbonate.  It  is  somewhat  less  irritating 


than  the  older  salt  since  it  does  not  form  the  basic 
carbonate.  It  has  been  used  as  an  expectorant  and 
a  carminative. 

Externally,  ammonium  bicarbonate  has  been 
applied  in  0.5  to  2  per  cent  aqueous  solution  for 
periodic  irrigation  of  suppurating  wounds  before 
granulations  fill  in  the  wound  (see  Berezin,  Am. 
Rev.  Soviet  Med.,  1945,  2,  230). 

The  dose  is  from  300  to  600  mg.  (approxi- 
mately 5  to  10  grains). 

AMMONIUM   BROMIDE.     N.F. 

[Ammonii  Bromidum] 

"Ammonium  Bromide,  dried  at  105°  for  2 
hours,  contains  not  less  than  99  per  cent  of 
NHiBr."  N.F. 

Ammonium  Bromatum;  Ammonium  Bromuretum;  Am- 
monium Hydrobromicum.  Fr.  Bromure  d'ammonium ; 
Bromhydrate  d'ammoniaque.  Ger.  Ammoniumbromid; 
Bromammonium.  It.  Bromuro  di  ammonio;  Bromidrato  di 
aniinoni.ua.  Sp.  Bromuro  de  amonio. 

Formerly  this  salt  was  prepared  by  dissolving 
bromine  in  ammonia  water,  the  hypobromite  pro- 
duced being  reduced  to  bromide  by  means  of 
hydrogen  sulfide.  An  early  pharmacopeial  process 
directed  preparation  of  the  salt  by  the  interaction 
of  ferrous  bromide  and  ammonia  water,  the  re- 
sulting ferrous  hydroxide  being  oxidized  to  ferric 
hydroxide  and  filtered  off,  and  the  ammonium 
bromide  obtained  by  evaporation  of  the  filtrate.  A 
present-day  commercial  method  of  preparing  the 
salt  involves  reaction  between  boiling  solutions 
of  ammonium  sulfate  and  potassium  bromide;  on 
cooling,  the  potassium  sulfate  precipitates  in  part, 
with  the  remainder  separating  on  concentration  of 
the  liquid,  aided  by  addition  of  alcohol.  The  am- 
monium bromide  is  obtained  from  the  residual 
liquid  by  concentrating  it  to  crystallize' the  salt. 

Description. — "Ammonium  Bromide  occurs 
as  colorless  crystals,  or  as  a  yellowish  white  crys- 
talline powder,  having  no  odor.  It  is  somewhat 
hygroscopic.  One  Gm.  of  Ammonium  Bromide 
dissolves  in  about  1.3  ml.  of  water  and  in  about 
12  ml.  of  alcohol."  N.F. 

Standards  and  Tests. — Identification. — A  1 
in  10  solution  of  ammonium  bromide  responds  to 
tests  for  ammonium  and  for  bromide.  Residue 
on  ignition. — Not  over  0.05  per  cent.  Acidity. — 
Not  more  than  0.05  ml.  of  0.1  N  sodium  hy- 
droxide is  required  to  neutralize  2  Gm.  of  ammo- 
nium bromide  in  20  ml.  of  water,  using  methyl 
red  T.S.  as  indicator.  Chloride. — In  the  assay, 
each  Gm.  of  ammonium  bromide  requires  not  less 
than  101.1  ml.  and  not  more  than  103.0  ml.  of 
0.1  N  silver  nitrate  in  the  assay.  Sulfate. — No  tur- 
bidity is  produced  in  1  minute  on  adding  barium 
chloride  T.S.  to  a  1  in  20  solution  of  ammonium 
bromide,  acidulated  with  hydrochloric  acid.  Ba- 
rium.— No  turbidity  is  produced  in  5  minutes  on 
adding  potassium  sulfate  T.S.  to  a  1  in  20  solution 
of  ammonium  bromide,  acidulated  with  hydro- 
chloric acid.  Heavy  metals. — The  limit  is  20  parts 
per  million.  Iron. — No  blue  color  is  produced  im- 
mediately on  adding  potassium  ferrocyanide  T.S. 
to  a  1  in  150  solution  of  ammonium  bromide. 
Bromate. — No  yellow  color  is  produced  immedi- 
ately on  adding  diluted  sulfuric  acid  to  powdered 
ammonium  bromide.  Iodide. — Not  even  a  tran- 


Part   I 


Ammonium   Carbonate 


77 


sient  violet  color  is  seen  in  the  chloroform  layer 
of  a  mixture  of  a  1  in  20  ammonium  bromide 
solution,  ferric  chloride  T.S.,  and  chloroform. 
N.F. 

Assay. — A  sample  of  about  400  mg.  of  ammo- 
nium bromide,  previously  dried  at  105°  for  2 
hours,  is  assayed  by  the  Volhard  method,  in 
which  a  measured  excess  of  0.1  AT  silver  nitrate 
is  employed;  the  excess  silver  ion  is  determined 
by  titration  with  0.1  N  ammonium  thiocyanate, 
using  ferric  ammonium  sulfate  T.S.  as  indicator. 
Each  ml.  of  0.1  N  silver  nitrate  represents 
9.796  mg.  of  NH4Br.  N.F. 

Uses. — Ammonium  bromide  is  useful  chiefly 
for  the  action  of  bromide  ion  (see  under  Potas- 
sium Bromide).  It  has  a  disagreeable  taste  and 
may  cause  digestive  disturbances.  According  to 
Dressier  {Clinical  Cardiology,  1942,  p.  186)  it  is 
preferable  to  ammonium  chloride  in  treatment 
of  edema  of  cardiac  origin,  being  better  tolerated 
and  having  the  two-fold  action  of  being  sedative 
to  the  central  nervous  system  and  producing  aci- 
dosis as  an  adjuvant  to  mercurial  diuresis.  For 
such  purpose  it  is  administered  in  doses  of  1  Gm. 
four  times  a  day  for  two  days  before  injection 
of  the  mercurial. 

Dose,  0.6  to  2  Gm.  (approximately  10  to  30 
grains)  well  diluted. 

Storage. — Preserve  "in  tight  containers." 
N.F. 

Off.  Prep. — Five  Bromides  Elixir;  Bromides 
Syrup;  Three  Bromides  Elixir;  Three  Bromides 
Tablets,  N.F. 


AMMONIUM   CARBONATE. 

[Ammonii  Carbonas] 


U.S.P. 


"Ammonium  Carbonate  consists  of  ammonium 
acid  carbonate  (NH4HCO3)  and  ammonium  car- 
bamate (NH2.COO.NH4)  in  varying  proportions, 
and  yields  not  less  than  30  per  cent  and  not  more 
than  33  per  cent  of  NH3."  U.S.P. 

Ammonia  Crystal;  Sal  Volatile.  Ammoniae  Carbonas;  Am- 
monium Carbonicum;  Ammonium  Sesquicarbonicum.  Fr. 
Carbonate  d'ammonium  officinal;  Sesquicarbonate  d'am- 
moniaque;  Alcali  volatil  concret.  Ger.  Ammoniumkarbonat ; 
Kohlensaures  Ammonium;  Hirschhornsalz;  Fluchtiges  Salz. 
It.  Carbonato  di  ammonio.  Sp.  Carbonato  de  amonio. 

As  is  apparent  from  the  official  definition,  "am- 
monium carbonate"  is  in  reality  a  mixture  of  am- 
monium bicarbonate  and  ammonium  carbamate. 
The  salt  is  prepared  by  heating  a  mixture  of  am- 
monium chloride  and  calcium  carbonate  in  iron 
pots  or  retorts;  the  "ammonium  carbonate"  vapor 
is  condensed  and  the  ammonium  vapor  is  con- 
ducted into  an  acid  solution.  The  reaction  may  be 
represented  as  follows: 

4NH4C1  +  2CaCOs  ->  NH4HCO3.NH2COONH4 
+  NH3  +  2CaCl2  +  H2O 

Ammonium  carbonate  can  also  be  prepared  by 
direct  reaction  of  ammonia,  carbon  dioxide  and 
steam. 

Description. — "Ammonium  Carbonate  occurs 
as  a  white  powder  or  as  hard,  white  or  translucent 
masses,  having  a  strong  odor  of  ammonia,  with- 
out empyreuma,  and  with  a  sharp,  ammoniacal 
taste.  Its  solutions  are  alkaline  to  litmus.  On  ex- 
posure to  air,  it  loses  ammonia  and  carbon  dioxide, 


becoming  opaque,  and  is  finally  converted  into 
friable,  porous  lumps  or  a  white  powder  of  am- 
monium bicarbonate.  One  Gm.  of  Ammonium 
Carbonate  dissolves  very  slowly  in  about  4  ml. 
of  water.  It  is  decomposed  by  hot  water."  U.S.P. 

Standards  and  Tests. — Identification. — Am- 
monium carbonate  volatilizes  without  charring 
when  heated;  the  vapor  is  strongly  alkaline  to 
moistened  litmus  paper.  Solutions  of  ammonium 
carbonate  effervesce  with  acids.  Residue  on  igni- 
tion.— Not  over  0.05  per  cent.  Chloride. — The 
limit  is  35  parts  per  million.  Sulfate. — The  limit 
is  50  parts  per  million.  Heavy  metals. — The  limit 
is  10  parts  per  million.  Emypreumatic  matter. — 
A  colorless,  odorless  residue  is  obtained  on  evapo- 
rating to  dryness  on  a  water  bath  a  nitric  acid 
solution  of  1  Gm.  of  ammonium  carbonate.  U.S.P. 

If  official  ammonium  carbonate  is  treated  with 
90  per  cent  alcohol,  it  is  resolved  into  the  two 
salts  of  which  it  is  composed,  ammonium  car- 
bamate going  into  solution  while  the  acid  ammo- 
nium carbonate  remains  undissolved.  The  latter 
compound  also  remains  undissolved  when  the  com- 
mercial carbonate  is  treated  with  an  amount  of 
water  insufficient  for  complete  solution.  Upon 
complete  solution  of  the  salt  in  water  there  re- 
sults a  mixture  of  acid  and  neutral  carbonates, 
the  carbamate  having  undergone  hydrolysis  ac- 
cording to  the  equation: 

NH2.COO.NH4  +  H2O  -»  (NHO2CO3 

Boiling  the  aqueous  solution  results  in  decomposi- 
tion of  the  compound  into  ammonia  and  carbon 
dioxide. 

Exposed  to  air,  ammonium  carbonate  is  gradu- 
ally converted  into  bicarbonate,  becoming  opaque 
and  friable,  and  changing  to  powder  form. 

Assay. — A  sample  of  about  2  Gm.  of  am- 
monium carbonate  is  dissolved  in  50  ml.  of  1  N 
sulfuric  acid,  and  the  excess  of  acid  is  titrated 
with  1  AT  sodium  hydroxide,  using  methyl  orange 
T.S.  as  indicator.  Each  ml.  of  1  A7  sulfuric  acid 
represents  17.03  mg.  of  NH3.  U.S.P. 

Uses. — Locally  ammonium  carbonate  is  an 
active  irritant  capable  of  causing  gastritis.  Sys- 
temically  its  action  is  that  of  its  ammonium 
radical.  When  injected  intravenously,  in  experi- 
mental studies  (since  it  is  not  injected  in  thera- 
peutics), the  blood  pressure  increases,  partly  from 
an  effect  on  the  cardiac  muscles,  and  probably 
also  in  part  from  a  stimulation  of  the  vasomotor 
center  in  the  medulla:  the  pressure  returns  to 
normal  in  a  very  few  minutes.  After  toxic  doses 
the  rise  may  be  followed  by  a  fall  to  a  point  below 
normal.  There  is  an  increase  in  the  rapidity  of 
breathing  due  to  an  action  upon  the  respiratory 
center.  The  action  upon  the  spinal  cord  is  shown 
by  increased  activity  of  reflexes;  in  sufficient 
doses  it  is  capable  of  causing  tetanic  convulsions. 
These  effects  are  caused  only  when  ammonium 
carbonate  is  injected  rapidly.  When  the  drug  is 
taken  by  mouth,  the  ammonium  ion  is  so  rapidly 
destroyed  in  the  system  that  it  is  scarcely  possi- 
ble for  a  sufficient  quantity  to  be  absorbed  through 
the  mucous  membrane  of  the  alimentary  tract. 
It  is  oxidized  in  the  liver  and  appears  in  the 
urine  chiefly  as  urea  (see  also  under  Ammonium 
Chloride) . 


m 


78 


Ammonium   Carbonate 


Part   I 


Ammonium  carbonate  has  been  used  as  a  car- 
minative in  "sick  headache."  It  is  also  employed 
as  an  expectorant  in  the  same  type  of  bronchitis 
in  which  ammonium  chloride  is  used;  the  car- 
bonate will  obviously  be  converted  to  chloride  in 
the  stomach  and  its  action  will  therefore  be  that 
of  the  chloride.  Coarsely  pulverized  and  mixed 
with  half  its  bulk  of  stronger  ammonia  water,  and 
usually  scented  with  oil  of  lavender,  it  constitutes 
the  common  smelling  salts  so  frequently  held 
under  the  nostrils  as  stimulant  in  syncope  and 
nervous  collapse.  It  is  unlikely  that  sufficient  am- 
monia can  be  absorbed  through  the  mucous  mem- 
brane to  exert  any  physiological  action,  and  as 
the  gas  is  irrespirable  it  cannot  be  inhaled.  The 
beneficial  action,  which  undoubtedly  occurs  in 
many  patients,  is  probably  due  to  a  reflex  effect 
from  irritation  of  the  nasal  mucous  membrane. 
Acetic  acid  vapors  are  used  for  the  same  purpose. 
A  similar  result  is  obtained  by  swallowing  a  solu- 
tion of  ammonium  carbonate,  as  in  the  popular 
aromatic  ammonia  spirit,  although  in  this  case 
the  reflex  comes  from  irritation  of  the  stomach 
instead  of  the  nose.  EO 

Ammonium  carbonate,  under  the  name  baker's 
ammonia,  is  sometimes  used  as  a  leavening  agent, 
replacing  sodium  bicarbonate. 

The  usual  dose  is  300  nig.  (approximately  5 
grains)  in  dilute  solution.  The  maximum  safe  dose 
is  usually  600  mg.  and  the  total  dose  in  24  hours 
should  seldom  exceed  2  Gm. 

Storage. — Preserve  "in  tight  containers,  pref- 
erably at  a  temperature  not  above  30°,  protected 
from' light."  U.S.P. 

Off.  Prep. — Aromatic  Ammonia  Spirit,  U.S.P., 
Ammonium  Acetate  Solution;  Bismuth  Magma; 
Expectorant  Mixture,  N.F. 

AMMONIUM  CHLORIDE.    U.S.P.,  B.P. 

[Ammonii  Chloridum] 

"Ammonium  Chloride,  dried  over  sulfuric  acid 
for  4  hours,  contains  not  less  than  99.5  per  cent 
of  NH4CI."  U.S.P.  The  B.P.  requires  not  less 
than  99.5  per  cent  of  NH4CI,  calculated  with 
reference  to  the  substance  dried  in  a  vacuum 
desiccator  over  sulfuric  acid  for  24  hours. 

Muriate  of  Ammonia.  Ammonium  Muriaticum;  Am- 
monium Chloratum;  Ammonium  Chloruretum;  Ammonium 
Hydrochloricum;  Chlorhydras  Ammoniac;  Ammonii  Chlor- 
urum.  Fr.  Chlorure  d'ammoniurn;  Chlorhydrate  d'am- 
moniaque;  Sel  ammoniac.  Ger.  Ammoniumchlorid;  Salmiak. 
It.  Cloruro  di  ammonio.  Sp.  Cloruro  de  amonio. 

Ammonium  chloride  originally  came  from 
Egypt,  where  it  was  obtained  by  sublimation 
from  the  soot  resulting  from  the  burning  of 
camels'  dung,  which  was  used  in  that  country  for 
fuel.  The  name  sal  ammoniac,  by  which  it  was 
first  known,  is  derived  from  the  fact  that  it  was 
largely  obtained  in  the  Libyan  desert  near  the 
temple  of  Jupiter  Ammon.  Ammonium  chloride 
has  long  been  known  in  China,  where  it  is  obtained 
from  the  water  of  certain  volcanic  springs.  It  is 
found  in  the  fumaroles  of  Vesuvius,  Etna,  Hecla, 
and  other  volcanoes,  and  in  the  cracks  and  fissures 
in  recent  lava  streams. 

Ammonium  chloride  is  commonly  prepared  by 
passing  ammonia  into  hydrochloric  acid.  Chief 
source  of  the  ammonia  is  ammoniacal  gas  liquor 


(see  Ammonia),  from  which  a  reasonably  pure 
ammonia  may  be  distilled  after  treatment  with 
lime.  Purification  of  the  ammonium  chloride 
may  be  effected  by  subliming  the  salt.  Ammonium 
chloride  may  also  be  prepared  by  the  interaction 
of  ammonia  and  hydrogen  chloride  vapors  in  the 
presence  of  some  water.  For  other  methods  which 
have  been  used  see  U.S.D.,  23rd  edition. 

Description. — "Ammonium  Chloride  occurs 
as  colorless  crystals  or  as  a  white,  fine  or  coarse, 
crystalline  powder.  It  has  a  cool,  saline  taste, 
and  is  somewhat  hygroscopic.  One  Gm.  of  Ammo- 
nium Chloride  dissolves  in  2.6  ml.  of  water,  in 
about  100  ml.  of  alcohol,  and  in  about  8  ml.  of 
glycerin.  One  Gm.  of  it  dissolves  in  1.4  ml.  of 
boiling  water."  U.S.P. 

Standards  and  Tests. — Identification. — A  1 
in  10  solution  of  ammonium  chloride  responds  to 
tests  for  ammonium  and  for  chloride.  Loss  on 
drying. — Not  over  0.5  per  cent,  when  dried  over 
sulfuric  acid  for  4  hours.  Residue  on  ignition. — 
Not  over  0.1  per  cent,  on  igniting  a  mixture  of  1 
ml.  of  sulfuric  acid  and  2  Gm.  of  ammonium 
chloride.  Acidity. — Not  more  than  0.05  ml.  of 
0.1  N  sodium  hydroxide  is  required  to  neutralize 
2  Gm.  of  ammonium  chloride  in  20  ml.  of  water, 
using  methyl  red  T.S.  as  indicator.  Thiocyanate. 
— Addition  of  a  few  drops  of  ferric  chloride  T.S. 
to  a  1  in  10  solution  of  ammonium  chloride,  acidu- 
lated with  hydrochloric  acid,  does  not  produce 
a  red  color.  Heavy  metals. — The  limit  is  10  parts 
per  million.  U.S.P.  The  B.P.  limits  loss  on  drying 
to  1.0  per  cent,  arsenic  to  4  parts  per  million, 
and  lead  to  5  parts  per  million. 

Assay. — About  200  mg.  of  ammonium  chlo- 
ride, previously  dried  over  sulfuric  acid  for  4 
hours,  is  assayed  by  a  modification  of  the  Volhard 
method  in  which  an  excess  of  0.1  N  silver  nitrate 
is  added,  and  the  excess  of  silver  ion  titrated 
directly,  without  filtering  off  the  silver  chloride, 
with  0.1  N  ammonium  thiocyanate,  using  ferric 
ammonium  sulfate  T.S.  as  indicator.  The  modifi- 
cation consists  in  adding  3  ml.  of  nitrobenzene 
prior  to  the  titration  with  ammonium  thiocyanate 
solution;  the  former  coats  the  particles  of  silver 
chloride  so  that  they  will  not  react  with  the 
thiocyanate  (see  Caldwell  and  Moyer,  Ind.  Eng. 
Chem.,  Anal.  Ed.,  1935,  7,  38).  Each  ml.  of  0.1  AT 
silver  nitrate  represents  5.350  mg.  of  NH4CI. 
U.S.P. 

The  B.P.  utilizes  the  classical  Volhard  assay, 
the  silver  chloride  being  removed  by  filtration 
before    titrating    with    thiocyanate. 

Incompatibilities. — Ammonium  chloride  is 
incompatible  with  lead  and  silver  salts,  producing 
precipitates  respectively  of  lead  and  silver  chlo- 
rides. With  alkalis,  as  well  as  with  substances 
which  in  aqueous  solution  produce  an  alkaline 
reaction,  ammonia  is  liberated.  This  incompati- 
bility is  shared  by  all  ammonium  salts. 

Uses. — Ammonium  chloride  is  most  commonly 
used  as  an  expectorant  and  as  a  diuretic;  it  is  an 
excellent  systemic  acidifying  agent.  It  possesses 
the  stimulant  qualities  of  its  basic  ion  and  re- 
sembles the  carbonate  in  its  physiologic  action. 

Acidifying  and  Diuretic  Actions. — Systemic 
effects  of  ammonium  chloride  depend  upon  the 
ability  of  the  liver  to  convert  ammonium  ion  into 


Part  I 


Ammonium   Chloride 


79 


urea,  thus  liberating  the  anion  into  the  blood 
stream  and  into  extracellular  fluids.  For  this  rea- 
son all  the  inorganic  salts  of  ammonium  increase 
the  acidity  of  the  urine.  One  gram  of  ammonium 
chloride  is  as  effective  as  a  urinary  acidifier  as 
2.5  Gm.  of  sodium  acid  phosphate  (see  J. A.M. A., 
1951,  147,  207).  It  is  used,  therefore,  in  those 
types  of  urinary  tract  infection  where  a  low  uri- 
nary pH  is  desired,  in  doses  of  6  to  8  Gm.  (ap- 
proximately V/i  to  2  drachms)  daily.  It  is  some- 
times administered  in  conjunction  with  methena- 
mine. 

According  to  Cornbleet  (J.A.M.A.,  1951,  146, 
1116),  the  excess  chloride  that  is  liberated  filters 
through  the  kidney  glomeruli,  which  the  tubules 
refuse  to  reabsorb  from  the  filtrate.  Some  of  the 
chloride  is  neutralized  by  sodium,  potassium  and 
calcium.  Compensatory  factors  acting  through  the 
posterior  lobe  of  the  pituitary  body  and  the 
adrenal  cortex  cause  an  equivalent  amount  of 
water  to  leave  with  the  sodium,  increasing  urine 
formation  and  promoting  diuresis.  Grollman  states 
that  the  acidosis  produced  by  ammonium  chloride 
causes  the  passage  of  intracellular  salts  and  water 
into  the  extracellular  spaces,  with  elimination  of 
this  tissue  fluid  by  the  kidney  (see  Modern  Medi- 
cine, June  1,  1951,  p.  59). 

One  of  the  uses  of  the  acidifying  quality  of  this 
drug  is  based  on  the  observation  of  Aub,  Minot 
and  Reznikoff  (Medicine,  1925,  4,  1)  that  diminu- 
tion of  the  pH  of  the  circulating  blood  renders 
calcium  more  soluble,  thus  promoting  decalcifica- 
tion. In  lead  poisoning  the  stored  lead  accom- 
panies calcium.  It  is  possible,  therefore,  to  "de- 
lead"  a  patient  with  lead  poisoning  by  the  admin- 
istration of  ammonium  chloride  in  1  Gm.  (ap- 
proximately 15  grains)  doses  each  hour  8  to  10 
times  daily,  together  with  a  diet  poor  in  calcium 
and  rich  in  phosphorus.  It  has  been  noted  by 
Brown,  Kolmer  and  Rule  (Am.  J.  Syph.,  1943, 
27,  501)  that  stored  bismuth,  resulting  from  its 
injection  for  the  treatment  of  syphilis,  may  be 
similarly  mobilized,  but  toxic  reactions  may  be 
encountered. 

A  frequent  use  of  ammonium  chloride  is  to 
promote  diuresis  in  many  conditions  characterized 
by  edema,  as  in  the  nephrotic  syndrome,  portal 
cirrhosis  of  liver,  and  congestive  heart  failure. 
Dosage  is  4  to  12  Gm.  (approximately  1  to  3 
drachms)  daily,  in  divided  quantities,  with  meals, 
usually  as  enteric-coated  tablets.  It  is  ordinarily 
given  in  courses  of  3  days,  with  equal  rest  periods 
to  minimize  gastric  irritation  and  diarrhea.  In 
the  edema  of  congestive  heart  failure  it  is  popu- 
larly administered  for  48  to  72  hours  prior  to 
giving  a  mercurial  diuretic  to  enhance  the  effect 
of  the  latter  (Etheridge,  Arch.  Int.  Med.,  1936, 
57,  514).  Stock  et  al.  (Circulation,  1951,  4,  54) 
state  that  its  synergistic  effect  when  so  used  is 
probably  due  to  its  ability  to  prevent  or  counter- 
act alkalosis.  Schroeder  (J.A.M.A.,  1951,  147, 
1109)  attributes  the  synergism  to  the  fact  that  the 
acidic  salts  cause  osmotic  tubular  diuresis  as  well 
as  increasing  the  renal  excretion  of  bases,  includ- 
ing sodium.  It  has  been  found  by  Greiner  and 
Gold  (JAM. A.,  1953,  152,  1130)  that  even  in  a 
dose  of  16  Gm.  ammonium  chloride  is  less  effec- 
tive as  a  diuretic  than  are  orally  administered 


theophylline  salts  and  organic  mercurials.  Addi- 
tional diuretic  indications  for  ammonium  chloride 
include  treatment  of  premenstrual  tension,  ther- 
apy of  Meniere's  syndrome  in  conjunction  with  a 
neutral  diet  (Furstenburg  et  al,  Ann.  Otol.  Rhin. 
Laryng.,  1934,  43,  1035),  and  in  certain  alcoholic 
states.  Cornbleet  (loc.  cit.)  treated  bromide  intoxi- 
cation successfully  with  ammonium  chloride,  since 
this  salt  furnishes  chloride  to  displace  the  bromide 
and  is  simultaneously  a  diuretic. 

Zintel,  Rhoads  and  Ravelin  (Surgery,  1943,  14, 
728)  reported  intravenous  use  of  ammonium 
chloride  in  alkalosis.  They  used  a  2  per  cent 
solution  in  normal  saline  or  in  5  per  cent  dextrose, 
the  maximum  rate  of  injection  being  1  liter  in 
2  hours.  A  1-Gm.  dose  is  said  to  reduce  the  serum 
carbon  dioxide-combining  power  in  a  150-pound 
adult  by  1.1  volume  per  cent.  The  solution  in 
saline  may  be  autoclaved  for  20  minutes  at  15 
pounds  pressure.  No  serious  reaction  is  reported 
although  there  may  be  chill  or  fever. 

Expectorant  Action. — Ammonium  chloride  is 
widely  prescribed  as  an  expectorant.  Being  non- 
volatile it  is  not  exhaled  through  the  pulmonary 
alveoli.  It  is  believed  that  reflex  stimulation  of 
the  bronchial  mucous  glands  results  from  irrita- 
tion of  the  gastric  mucosa.  Perry  and  Boyd 
(/.  Pharmacol.,  1941,  73,  65)  demonstrated  an 
increase  in  bronchial  secretion  by  reflex  action 
from  the  stomach,  there  being  no  response  to 
introduction  of  ammonium  chloride  after  severing 
branches  of  the  vagus  nerve  supplying  the 
stomach.  Banyai  states  (J.A.M.A.,  1952,  148, 
501)  that,  in  addition  to  reducing  viscosity  and 
pH  and  increasing  fluidity  of  the  bronchial  secre- 
tions, the  drug  stimulates  the  ciliary  function  of 
the  mucosa.  A  dose  of  300  mg.  every  2  hours  is 
used  in  a  syrup;  tablets  should  not  be  enteric- 
coated.  Flavored  lozenges  containing  the  drug  are 
sometimes  prescribed  in  pharyngitis  and  laryngitis 
to  secure  both  a  local  effect  and  an  effect  from 
the  medicated  saliva  that  is  swallowed. 

Local  Anesthetic  Action. — A  new  use  for 
ammonium  chloride  has  been  described  by  Judo- 
vich,  Bates  and  Bishop  (Anesth.,  1944,  5,  341), 
based  on  earlier  investigation  of  a  preparation  of 
the  pitcher  plant,  Sarracenia  purpurea,  made  by 
distillation  of  the  powdered  rhizome  in  the  pres- 
ence of  caustic  alkali  and  used  in  the  relief  of 
neuralgic  pain.  Neutralization  of  the  distillate 
with  hydrochloric  or  sulfuric  acid  yields  salts 
found  to  be  identical  with  ammonium  chloride 
and  ammonium  sulfate,  respectively  (see  Stewart 
et  al,  Am.  J.  Physiol,  1940,  129,  474;  Walti, 
J.A.C.S.,  1945,  67,  2271).  Following  preliminary 
sedation  of  the  patient  with  morphine,  atropine 
and  amytal,  from  3  to  5  ml.  of  a  6  per  cent  solu- 
tion of  ammonium  chloride,  adjusted  to  pH  7.2 
by  means  of  sodium  hydroxide,  is  mixed  with 
50  ml.  of  cerebrospinal  fluid  and  injected  intra- 
spinally.  Such  administration  is  limited  to  patients 
with  root  pain  of  metastatic  origin. 

Toxicology. — Among  the  more  severe  toxic 
reactions  to  ammonium  chloride,  acidosis  has 
been  reported  by  Sleisinger  and  Freedberg  (Circu- 
lation, 1951,  3,  837),  during  its  administration 
as  a  diuretic.  They  believed  the  severe  acidosis 
to  be  related  to  intrinsic  renal  disease  and  the 


80 


Ammonium    Chloride 


Part   I 


inability  of  the  kidneys  to  prevent  continued  loss 
through  the  urine  of  fixed  base  with  chloride.  The 
drug  may  also  precipitate  uremia  when  used  in 
the  presence  of  renal  disease. 

According  to  Purdum  (7.  A.  Ph.  A.,  1942,  31, 
298)  syrups  of  glycyrrhiza,  raspberry,  orange 
flowers,  citric  acid  and  tolu  balsam  are  the  most 
effective  masking  vehicles  for  the  disagreeable 
salty  taste  of  ammonium  chloride.  An  aromatic 
syrup  of  ammonium  chloride,  prepared  by  Sorg 
and  Kuever  (/.  A.  Ph.  A.,  Pract.  Ed.,  1942,  3, 
262)  especially  for  use  in  Furstenberg's  treatment 
of  Meniere's  disease,  has  the  following  composi- 
tion: Ammonium  chloride,  200  Gm.;  soluble  sac- 
charin, 10  Gm.;  menthol,  1  Gm.;  alcohol,  30  ml.; 
glycerin,  100  ml.;  compound  syrup  of  sarsaparilla, 
400  ml.;  distilled  water,  to  1000  ml.  (3 

The  usual  dose  is  1  Gm.  (approximately  15 
grains),  by  mouth,  4  times  a  day,  with  a  range 
of  300  mg.  to  2  Gm.;  the  maximum  safe  dose  is 
2  Gm.,  and  the  total  dose  in  24  hours  exceeds 
8  Gm.  only  under  certain  conditions  (v.s.).  As 
an  expectorant,  300  mg.  (approximately  5  grains) 
is  used  as  frequently  as  every  two  hours. 

Storage. — Preserve  "in  tight  containers." 
U.S.P. 

AMMONIUM  CHLORIDE  CAPSULES 

U.S.P. 

[Capsulse  Ammonii  Chloridi] 

"Ammonium  Chloride  Capsules  contain  not  less 
than  93  per  cent  and  not  more  than  107  per  cent 
of  the  labeled  amount  of  NH4CI."  U.S.P. 

Sp.  Cdpsulas  de  Cloruro  de  Amonxo. 

Assay. — The  contents  of  not  less  than  20  cap- 
sules are  transferred  to  a  500-ml.  volumetric 
flask,  the  emptied  capsules  being  washed  with 
water  and  this  solution  filtered  into  the  same 
volumetric  flask.  After  diluting  to  500  ml.  an 
aliquot  portion,  equivalent  to  about  200  mg.  of 
ammonium  chloride,  is  transferred  to  a  distilling 
flask,  alkalinized  with  10  per  cent  sodium  hydrox- 
ide solution,  and  the  ammonia  distilled  into  a 
boric  acid  solution.  The  ammonia  in  this  solution 
is  titrated  with  0.1  N  sulfuric  acid,  using  methyl 
red  T.S.  as  indicator.  A  blank  test  is  performed 
on  the  reagents  and  any  necessary  correction  ap- 
plied. Each  ml.  of  0.1  N  sulfuric  acid  represents 
5.350  mg.  of  NH4CI.  U.S.P. 

Storage. — Preserve  "in  tight  containers." 
U.S.P. 

Usual  Sizes. — 5  and  ll/z  grains  (approxi- 
mately 300  and  500  mg.). 

AMMONIUM   CHLORIDE  TABLETS. 
N.F. 

[Tabellae  Ammonii  Chloridi] 

"Ammonium  Chloride  Tablets  contain  not  less 
than  94  per  cent  and  not  more  than  106  per  cent 
of  the  labeled  amount  of  NH4CI  for  tablets  of 
300  mg.  or  more,  and  not  less  than  92.5  per  cent 
and  not  more  than  107.5  per  cent  for  tablets  of 
less  than  300  mg."  N.F. 

Usual  Sizes. — 5  and  lYz  grains  (approxi- 
mately 300  and  500  mg.),  frequently  enteric 
coated. 


AMMONIUM   IODIDE.     N.F. 

[Ammonii  Iodidum] 

"Ammonium  Iodide  dried  at  105°  for  2  hours 
contains  not  less  than  98  per  cent  of  NH4I.  It 
may  contain  not  more  than  one  per  cent  of  am- 
monium hypophosphite  as  a  stabilizing  agent." 
N.P. 

Ammonium  Jodatum;  Jodetum  Ammonicum;  Ammonium 
Hydrojodicum.  Fr.  Jodure  d'ammonium.  Ger.  Ammonium- 
jodid;  Jodammonium.  It.  Joduro  di  amnionic  Sp.  Voduro 
de  amonio. 

Several  methods  of  preparing  ammonium  iodide 
are  available.  The  one  probably  most  often  em- 
ployed is  that  involving  the  interaction  of  am- 
monium sulfate  and  potassium  iodide;  the  potas- 
sium sulfate  precipitates  on  cooling  the  mixture 
and  adding  some  alcohol  to  it,  and  the  ammonium 
iodide  is  obtained  on  evaporating  the  liquid  phase. 
Other  methods  of  making  ammonium  iodide  in- 
volve neutralization  of  hydriodic  acid  by  am- 
monia, interaction  between  ferrous  iodide  and 
ammonium  carbonate,  or  between  potassium 
iodide  and  ammonium  bitartrate. 

Description. — "Ammonium  Iodide  occurs  as 
minute,  colorless,  cubic  crystals,  or  as  a  white, 
granular  powder.  It  is  odorless,  and  has  a  sharp, 
salty  taste.  Ammonium  Iodide  is  very  hygro- 
scopic, and  soon  becomes  yellow  or  yellowish 
brown  on  exposure  to  air  and  light,  owing  to  the 
loss  of  ammonia  and  the  liberation  of  iodine,  if  no 
stabilizing  agent  is  added.  Its  solutions  are  neutral 
or  acid  to  litmus  paper.  One  Gm.  of  Ammonium 
Iodide  dissolves  in  about  0.6  ml.  of  water,  in 
about  3.7  ml.  of  alcohol,  and  in  about  1.5  ml.  of 
glycerin,  at  25°.  One  Gm.  also  dissolves  in  about 
0.5  ml.  of  boiling  water."  N.F. 

Standards  and  Tests. — Identification. — A  1 
in  20  solution  of  ammonium  iodide  responds  to 
tests  for  ammonium  and  for  iodide.  Loss  on  dry- 
ing.— Not  over  5  per  cent,  when  dried  at  105°  for 
2  hours.  Residue  on  ignition. — Not  over  0.5  per 
cent  (strong  heating  decomposes  the  salt  with 
evolution  of  iodine  vapor  and  volatilization  with- 
out fusing).  Chloride. — In  the  assay,  each  Gm.  of 
ammonium  iodide  consumes  not  less  than  67.6  ml. 
and  not  more  than  69.0  ml.  of  0.1  N  silver  nitrate. 
Free  iodine. — Not  even  a  transient  violet  color 
appears  in  chloroform  when  it  is  shaken  with 
5  volumes  of  1  in  150  solution  of  ammonium 
iodide.  Barium. — No  turbidity  is  produced  in  5 
minutes  on  adding  a  1  in  10  solution  of  sodium 
sulfate  to  5  volumes  of  a  1  in  20  solution  of  am- 
monium iodide  which  has  been  acidulated  with 
hydrochloric  acid.  Heavy  metals. — The  limit  is 
20  parts  per  million.  N.F. 

Assay. — The  Volhard  method  is  employed  in 
assaying  ammonium  iodide;  an  excess  of  0.1  N 
silver  nitrate  is  added  to  about  500  mg.  of  am- 
monium iodide,  previously  dried  at  105°  for  2 
hours,  the  mixture  heated  until  the  precipitate 
has  a  yellow  color  and,  after  cooling,  the  residual 
silver  nitrate  is  estimated  by  titration  with  0.1  N 
ammonium  thiocyanate  using  ferric  ammonium 
sulfate  T.S.  as  indicator.  Each  ml.  of  0.1  N  silver 
nitrate  represents  14.50  mg.  of  NH4I.  N.F. 

Uses. — Ammonium  iodide  has  been  used  like 
potassium   iodide    (see   Potassium   Iodide,    also 


Part  I 


Amobarbital 


81 


Iodine).  It  was  especially  recommended  in  chronic 
bronchitis  and  in  asthma,  with  the  thought  of 
combining  the  resolvent  action  of  the  iodide  and 
the  expectorant  effect  of  ammonium.  Pennock 
used  it  in  cases  of  lepra  and  psoriasis,  in  the  form 
of  a  4  to  12  per  cent  ointment.  As  the  iodide  is 
decomposed  by  air,  the  ointment  should  be  kept 
in  well-stoppered  bottles.  |v] 

Dose,  from  200  to  600  mg.  (approximately  3  to 
10  grains). 

Storage. — Preserve  "in  tight,  light-resistant 
containers."  N.F. 


AMMONIUM  SALICYLATE.     N.F. 

[Ammonii  Salicylas] 

"Ammonium  Salicylate,  dried  over  sulfuric 
acid  for  4  hours,  contains  not  less  than  98 
per  cent  of  C7H5NH4O3."    N.F. 

Ammonium  Salicylicum.  Fr.  Salicylate  d'ammonium. 
Ger.  Ammoniumsalicylat;  Salicylsaures  Ammonium.  It. 
Salicilato  di  ammonio.  Sp.  Salicilato  de  amonio. 

This  salt  may  be  made  by  adding  salicylic 
acid  to  ammonia  water  until  the  acid  is  in  slight 
excess,  then  evaporating  the  solution  and  crystal- 
lizing. Contamination  with  iron  gives  the  product 
a  pinkish  or  reddish  tinge;  overheating  results  in 
the  salt  having  a  phenol-like  odor. 

Description. — "Ammonium  Salicylate  occurs 
as  colorless,  lustrous  prisms,  or  plates,  or  as  a 
white  crystalline  powder  having  a  faint  pink 
tinge.  It  is  odorless,  and  has  at  first  a  slightly 
salty,  bitter  taste,  with  a  sweet  aftertaste.  It  is 
stable  in  dry  air,  but  is  affected  by  light.  One 
Gm.  of  Ammonium  Salicylate  dissolves  in  about 
1  ml.  of  water  and  in  about  3  ml.  of  alcohol."  N.F. 

Standards  and  Tests. — Identification. — Am- 
monium salicylate  responds  to  tests  for  ammonium 
and  for  salicylate.  Acidity. —  Not  more  than  0.4 
ml.  of  0.1  N  sodium  hydroxide  is  required  to 
neutralize  1  Gm.  of  ammonium  salicylate,  using 
methyl  red  T.S.  as  indicator.  Residue  on  ignition. 
— Not  over  0.05  per  cent.  Heavy  metals. — The 
limit  is  10  parts  per  million.  N.F. 

Assay. — About  500  mg.  of  ammonium  salicyl- 
ate, previously  dried  over  sulfuric  acid  for  4 
hours,  is  titrated  with  0.1  iV  hydrochloric  acid  in 
the  presence  of  ether.  The  acid  displaces  sali- 
cylic acid  which  dissolves  in  the  ether  layer;  an 
equivalent  amount  of  ammonium  chloride  is 
formed  in  the  aqueous  phase.  Because  a  small 
amount  of  salicylic  acid  remains  dissolved  in  the 
aqueous  phase  it  is  necessary,  when  the  first 
end-point  is  reached,  to  replace  the  ether  layer 
by  a  fresh  portion  of  ether  to  extract  the  salicylic 
acid  in  the  aqueous  layer;  the  titration  is  con- 
tinued until  the  bromophenol  blue  indicator  shows 
a  permanent  pale  green  color  in  the  aqueous  layer. 
Each  ml.  of  0.1  N  hydrochloric  acid  represents 
15.52  mg.  of  C7H5NH4O3.  N.F. 

Uses. — Ammonium  salicylate  was  at  one  time 
thought  to  be  one  of  the  best  forms  of  adminis- 
tering salicylic  acid  internally  but  it  is  seldom 
used  at  present.  For  discussion  of  its  uses,  see 
under  Acetylsalicylic  Acid  and  Sodium  Salicylate. 

Dose,  from  0.6  to  1.3  Gm.  (approximately  10 
to  20  grains). 


Storage. — Preserve   "in   tight,   light-resistant 
containers,  and  avoid  excessive  heat."  N.F. 

AMOBARBITAL.     U.S.P. 

5-Ethyl-5-isoamylbarbituric  Acid,  [Amobarbitalum] 


HN 
HN 


y~\ws 


^/^CHgCHgCHtCH^j 


Amylobarbitone,  B.P.C.  Amytal  (Lilly). 

Amobarbital  may  be  prepared  by  the  general 
procedure  for  producing  barbiturates,  namely,  by 
condensation  of  the  proper  substituted  malonic 
ester  with  urea;  in  this  instance  the  ester  is 
isoamylethylmalonic  ester.  Condensation  is  ef- 
fected in  an  autoclave  in  the  presence  of  sodium 
ethylate  (see  Shonle  and  Moment,  J.A.C.S.,  1923, 
45,  243;  U.  S.  Patent  1,514,573,  November  4, 
1924). 

Description. — "Amobarbital  occurs  as  a 
white  crystalline  powder.  It  is  odorless  and  has  a 
bitter  taste.  Its  solutions  are  acid  to  litmus  paper. 
One  Gm.  of  Amobarbital  dissolves  in  about 
1300  ml.  of  water,  in  5  ml.  of  alcohol,  in  about 
17  ml.  of  chloroform,  and  in  6  ml.  of  ether.  It  is 
soluble  in  solutions  of  fixed  alkali  hydroxides  and 
carbonates.  Amobarbital  melts  between  156°  and 
158.5°.  U.S.P. 

Standards  and  Tests. — Identification. — (1) 
Ammonia  is  evolved  on  heating  amobarbital  with 
sodium  hydroxide  T.S.  (2)  The  />-nitrobenzyl 
derivative  melts  between  151°  and  154°.  Loss 
on  drying. — Not  over  1  per  cent,  when  dried  over 
sulfuric  acid  for  4  hours.  Residue  on  ignition. — 
Not  over  0.1  per  cent.  Readily  carbonizable  sub- 
stances.— A  solution  of  500  mg.  of  amobarbital 
in  5  ml.  sulfuric  acid  has  no  more  color  than 
matching  fluid  A.  U.S.P. 

Uses. — Amobarbital,  introduced  as  Amytal,  is 
a  barbiturate  of  moderate  duration  of  action.  It 
has  the  advantage  over  barbital  and  phenobarbi- 
tal  of  being  destroyed  in  the  body  and  since  its 
elimination  does  not  depend  on  the  kidneys  amo- 
barbital is  preferable  to  the  two  other  barbitu- 
rates for  administration  to  patients  with  kidney 
disease.  For  a  comparison  of  duration  of  action 
and  metabolism  of  amobarbital  see  the  mono- 
graph on  Barbiturates,  in  Part  II. 

For  parenteral  administration  the  water-soluble 
sodium  derivative,  in  sterile  form,  is  employed; 
the  latter  may  also  be  given  orally  and,  some- 
times, rectally.  Amobarbital  sodium  is  the  drug 
of  choice  when  a  longer  period  of  action  is  de- 
sired during  the  gradual  induction  of  narcosis 
in  a  patient  to  be  interviewed  by  the  technique 
of  "narcosynthesis"  or  "narcoanalysis"  (see  also 
under  Thiopental  Sodium) ;  for  a  review  of  this 
use  of  amobarbital  sodium  see  Lipton  {American 
Practitioner,  1950,  1,  148).  According  to  Miller 
{Arch.  Neurol.  Psychiat.,  1952,  67,  620)  simulta- 
neous use  of  ethyl  alcohol  improves  the  incidence 
of  success  in  narcoanalysis  by  decreasing  somno- 
lence and  increasing  talkativeness  while  also 
decreasing  the  dose  of  amobarbital  sodium  re- 


82 


Amobarbital 


Part  I 


quired;  from  120  to  300  mg.  of  amobarbital 
sodium,  depending  on  the  weight  of  the  patient, 
is  dissolved  in  20  to  25  ml.  of  isotonic  sodium 
chloride  solution  containing  10  to  15  per  cent 
of  alcohol  and  the  solution  administered  intrave- 
nously over  a  period  of  2  to  4  minutes. 

Its  moderate  vasodepressor  effect  seems  to  be 
useful  for  the  purpose  of  diagnosing  phenochro- 
mocytoma  (Anderson  et  al.,  Am.  Heart  J.,  1952, 
43,  252). 

Administered  intravenously  (230  to  500  mg.), 
amobarbital  sodium  produced  a  significant  de- 
pression of  oxygen  uptake  by  the  brain,  a  lower- 
ing of  blood  flow,  and  a  mild  depression  of  mean 
arterial  pressure  in  the  eclamptic  patient;  this 
may  be  an  advantage  in  the  preeclamptic  patient 
for  the  prevention  of  seizures  but  may  add  to  the 
depression  produced  by  convulsions  in  the  ad- 
vanced case  (McCall  and  Tavlor,  J.A.M.A.,  1952, 
149,   51). 

Combined  with  amphetamine,  amobarbital  has 
been  reported  to  neutralize  extremes  of  moods, 
giving  the  depressed  patient  a  more  normal  out- 
look and  behavior  (Grahn,  American  Practitioner , 
1950,  1,  795). 

The  usual  dose  of  amobarbital  is  100  mg.  (ap- 
proximately iy2  grains)  once  or  twice  daily,  by 
mouth,  with  a  range  of  20  to  300  mg.  The  maxi- 
mum safe  dose  is  usually  500  mg..  and  the  total 
dose  during  24  hours  should  seldom  exceed  1  Gm. 
When  used  as  a  sedative  it  is  given  in  doses  of 
20  to  50  mg.;  as  a  hypnotic  the  dose  is  100  to 
300  mg. 

Storage. — Preserve  "in  well-closed  contain- 
ers." U.S.P. 

AMOBARBITAL  ELIXIR.     N.F. 

[Elixir  Amobarbitali] 

"Amobarbital  Elixir  contains,  in  each  100  ml., 
not  less  than  417  mg.  and  not  more  than  462  mg. 
of  CiiHi8N203."  N.F. 

Dissolve  4.4  Gm.  of  amobarbital,  1  Gm.  of  sac- 
charin sodium,  0.26  ml.  of  orange  oil,  0.15  ml. 
of  lemon  oil,  0.03  ml.  of  cinnamon  oil,  0.006  ml.  of 
caraway  oil,  0.0018  ml.  of  coriander  oil,  0.02  ml. 
of  anise  oil,  and  0.02  ml.  of  sassafras  oil  in  300 
ml.  of  alcohol.  To  this  solution  add  310  ml.  of 
propylene  glycol,  4.4  Gm.  of  methenamine,  11.25 
ml.  of  caramel,  and  enough  purified  water  to 
make  1000  ml.  Mix  well,  allow  the  product  to 
stand  24  hours,  and  filter  until  it  is  clear.  N.F. 
The  purpose  of  the  methenamine  is  to  increase 
the  solubility  of  the  amobarbital. 

Assay. — A  25-ml.  portion  of  elixir  is  alkalin- 
ized  with  sodium  hydroxide  T.S.  and  shaken  with 
petroleum  benzin  to  remove  the  flavoring  oils; 
after  washing  the  petroleum  benzin  with  water 
it  is  discarded.  The  alkaline  solution  is  acidified 
with  hydrochloric  acid  and  the  amobarbital  ex- 
tracted with  several  portions  of  ether.  The 
washed  ether  extraction  is  evaporated  to  dryness, 
dried  at  105°.  and  weighed.  N.F. 

Alcohol  Content. — From  27  to  33  per  cent, 
by  volume,  of  C2H5OH.  N.F. 

The  N.F.  gives  the  usual  dose  as  4  ml.  (ap- 
proximately 1  fluidrachm),  representing  17.6  mg. 
(approximately  l/i  grain)  of  amobarbital. 


Storage. — Preserve  "in  tight  containers." 
N.F. 

AMOBARBITAL  TABLETS.  U.S.P. 

"Amobarbital  Tablets  contain  not  less  than  94 
per  cent  and  not  more  than  106  per  cent  of  the 
labeled  amount  of  C11H18N2O3."  U.S.P. 

The  tablets  are  assayed  by  a  modification  of 
the  procedure  described  under  Barbital  Tablets. 

Usual  Sizes.— 8,  15,  30,  50,  and  100  mg.  (l/s, 
lA,  y2,  Ya  and  \Vz  grains). 

AMOBARBITAL  SODIUM.     U.S.P. 

[Amobarbitalum  Sodicum] 

"Amobarbital  Sodium  contains  not  less  than 
98.5  per  cent  of  CiiHi7N2Na03,  calculated  on 
the  dried  basis."  U.S.P. 

Amylobarbitone  Sodium,  B.P.C.  Sodium  Isoamylethyl- 
barbiturate.  Amytal  Sodium  (Lilly). 

The  sodium  derivative  of  amobarbital  may  be 
obtained  by  the  interaction  of  sodium  hydroxide 
or  sodium  carbonate  with  amobarbital. 

Description. — "Amobarbital  Sodium  occurs 
as  a  white,  friable,  granular  powder.  It  is  odorless, 
has  a  bitter  taste,  and  is  hygroscopic.  Its  solutions 
are  alkaline  to  litmus  and  to  phenolphthalein. 
Amobarbital  Sodium  is  very  soluble  in  water, 
soluble  in  alcohol,  but  practically  insoluble  in 
ether  and  in  chloroform."  U.S.P. 

Standards  and  Tests. — Identification. — (1) 
The  amobarbital  obtained  in  the  assay  melts  be- 
tween 156°  and  158.5°  and  responds  to  the  iden- 
tification tests  under  Amobarbital.  (2)  The  resi- 
due from  the  ignition  of  amobarbital  sodium  ef- 
fervesces with  acids  and  responds  to  the  tests  for 
sodium.  Loss  on  drying. — Not  over  1  per  cent, 
when  determined  by  drying  at  105°  for  4  hours. 
Heavy  metals. — The  limit  is  30  parts  per  million. 
Free  amobarbital. — Not  over  0.5  per  cent,  the 
amobarbital  being  extracted  with  benzene  and  the 
residue  after  evaporation  of  the  benzene  dried  at 
105°  for  30  minutes.  U.S.P. 

Assay. — A  solution  of  1  Gm.  of  amobarbital 
sodium  in  15  ml.  of  water  is  acidified  with  hydro- 
chloric acid  and  the  liberated  amobarbital  is 
extracted  with  chloroform.  The  chloroform  ex- 
tract is  filtered,  evaporated  to  dryness,  and  the 
residue  of  amobarbital  is  dried  at  105°  for  30 
minutes  and  weighed.  The  weight  of  the  residue, 
multiplied  by  1.097,  represents  CnHuNaNaOs. 
U.S.P. 

Uses. — Amobarbital  sodium,  being  soluble  in 
water,  is  the  form  in  which  the  barbiturate  is 
administered  parenterally;  it  may  also  be  given 
orally.  For  parenteral  use  the  sterile  powder,  sup- 
plied in  ampuls,  is  used  to  make  the  solution  and 
this  must  be  prepared  immediately  before  use  in 
order  to  avoid  hydrolytic  decomposition  of  the 
barbiturate.  A  rectal  suppository,  containing 
200  mg.  of  amobarbital  sodium,  is  also  available. 
The  uses  are  discussed  under  Amobarbital. 

Dose. — The  usual  dose  is  100  mg.  (approxi- 
mately 1^2  grains)  once  or  twice  daily  by  mouth 
or  per  rectum  or,  in  a  5  or  10  per  cent  solution, 
intramuscularly  or  subcutaneousiy.  The  range  of 
dose  is  20  to  500  mg.  The  maximum  safe  dose 


Part  I 


Amodiaquine   Hydrochloride  83 


is  usually  500  mg.  and  a  total  dose  of  1  Gm.  is 
seldom  exceeded  in  a  24-hour  period.  When  used 
as  a  preanesthetic  sedative  as  much  as  600  mg. 
(approximately  9  grains)  may  be  given.  As  an 
anticonvulsant  in  tetanus  800  mg.  (approximately 
12  grains)  may  be  required.  In  emergencies  it  is 
given  intravenously  with  great  caution  (not  over 
1  ml.  per  minute  of  a  5  or  10  per  cent  solution). 
Storage. — Preserve  "in  tight  containers." 
U.S.P. 

AMOBARBITAL  SODIUM  CAPSULES. 
U.S.P. 

"Amobarbital  Sodium  Capsules  contain  not 
less  than  90  per  cent  and  not  more  than  105  per 
cent  of  the  labeled  amount  of  CnHi7N2Na03." 
c7-SJP- 

Usual  Sizes.— 60  and  200  mg.  (1  and  3 
grains). 

STERILE  AMOBARBITAL  SODIUM. 
U.S.P. 

"Sterile  Amobarbital  Sodium  contains  not  less 
than  98.5  per  cent  of  CuHn^NaOs,  calculated 
on  the  dried  basis."  U.S.P. 

This  is  the  sterile  powder  from  which  injectable 
solutions  of  amobarbital  sodium  are  prepared  by 
addition  of  water  for  injection. 

Usual  Sizes.— 65,  125,  250,  500,  and  750  mg., 
and  1  Gm. 

AMODIAQUINE  HYDROCHLORIDE. 
LP. 

Amodiaquini  Hydrochloridum 
C20H22ON3Cl.2HCl.2H2O 

Amodiaquine  Hydrochloride  is  7-chloro-4-(3'- 
diethylaminomethyl  -  4'  -  hydroxyanilino)quinoline 
dihydrochloride  clihydrate.  It  contains  not  less 
than  98.0  per  cent  and  not  more  than  the  equiv- 
alent of  100.0  per  cent  of  C20H22ON3CI.2HCL- 
2H20.  LP. 

Camoquin  Hydrochloride  (Parke,  Davis).  Miaquin. 
CAM-AQ1.   SN   10,751. 

This  antimalarial  agent  is  of  the  4-aminoquino- 
line  type  (see  article  on  Antimalarial  Agents,  in 
Part  II)  and  hence  is  related  to  chloroquine.  It 
may  be  prepared  from  4,7-dichloroquinoline  and 
4-acetamido-a-diethylamino-o-cresol;  for  details 
of  synthesis  see  Burckhalter  et  al.  (J.A.C.S.,  1948, 
70,  1363),  also  U.  S.  Patents  2,474,819  and 
2,474,821  (1949). 

Description. — Amodiaquine  Hydrochloride  oc- 
curs as  a  yellow,  crystalline  powder;  it  is  odorless 
and  has  a  better  taste.  It  is  soluble  in  about  22 
parts  of  water;  soluble  in  alcohol.  It  melts  be- 
tween 154°  and  157°,  with  decomposition.  LP. 

Standards  and  Tests. — Identification. — (1) 
The  amodiaquine  base  obtained  in  the  assay  melts 
between  205°  and  209°,  with  decomposition.  (2) 
Amodiaquine  hydrochloride  responds  to  tests  for 
chlorides.  Residue  on  ignition. — Not  over  0.2  per 
cent.  LP. 

Assay. — About  300  mg.  of  amodiaquine  hy- 
drochloride is  dissolved  in  water,  the  solution  is 
made  alkaline  with  ammonia  T.S.  and,  after  the 


mixture  has  been  allowed  to  stand  for  not  less 
than  30  minutes,  the  precipitated  amodiaquine 
base  is  collected  in  a  glass  filtering  crucible,  dried 
at  110°  for  3  hours,  and  weighed.  LP. 

Uses. — Amodiaquine  hydrochloride  is  a  sup- 
pressive antimalarial  drug  with  action  similar  to 
that  of  chloroquine  (see  Chloroquine  Phosphate)  ; 
it  has  the  advantages  of  increased  effectiveness  in 
a  single  dose  and  of  lesser  toxicity.  It  is  rapidly 
absorbed  from  the  gastrointestinal  tract.  A  thera- 
peutic concentration  is  attained  in  the  blood 
within  1  hour  of  its  ingestion.  As  with  chloroquine, 
the  highest  concentration  of  the  drug  is  found  in 
the  liver.  Erythrocytes  contain  twice  the  concen- 
tration in  blood  plasma,  which  latter  is  about  190 
micrograms  per  liter  on  a  dose  of  300  mg.  daily. 
It  remains  in  the  tissues  for  at  least  a  week  after 
a  single  dose.  Less  than  5  per  cent  is  excreted  in 
the  urine.  In  the  form  of  a  5  per  cent  aqueous 
solution  it  may  be  given  intramuscularly  with 
only  slight  induration  resulting  (Payne  et  al.,  Am. 
J.  Trop.  Med.,  1949,  29,  353)  or  intravenously 
(Payne  et  al,  ibid.,  1951,  31,  698).  After  slow  in- 
jection intravenously  of  150  or  300  mg.  of  the 
dihydrochloride  only  a  trivial  decrease  in  blood 
pressure  was  observed. 

Antimalarial  Action. — Amodiaquine  is  an 
effective  suppressive  drug  (Coggeshall,  Am.  J. 
Trop.  Med.  Hyg.,  1952,  1,  124)  and  it  rapidly 
controls  fever  and  parasitemia  in  patients  infected 
with  P.  falciparum,  P.  vivax,  or  P.  malariae 
(Chaudhuri,  Indian  Med.  Gaz.,  1948,  83,  225; 
Singh  and  Kalyanum,  Brit.  M.  J.,  1952,  2,  312; 
Hoekenga,  J. A.M. A.,  1952,  149,  1369;  Love  et 
al,  Am.  J.  Med.  Sc,  1953,  225,  26).  It  does  not 
affect  the  gametocytes  of  P.  falciparum  or  the 
tissue  stage  of  P.  vivax,  but  its  tendency  to  re- 
main in  the  body  for  some  time  delays  the  relapse 
in  P.  vivax  infestations,  particularly  in  partially 
immune  persons.  Its  efficacy  in  a  single  dose  and 
the  rarity  of  toxic  manifestations  are  its  chief 
advantages.  Reports  of  its  value  have  appeared 
from  all  parts  of  the  world.  Doses  have  varied 
widely  but  10  mg.  per  Kg.  of  body  weight,  or  an 
average  of  600  mg.  for  an  adult  in  a  single  dose, 
seems  to  be  adequate.  Several  studies  indicate 
that  a  single  dose  is  more  effective  than  the  same 
quantity  in  divided  doses  over  a  period  of  24  to 
120  hours  (Chaudhuri  and  Chakravarty,  Indian 
J.  Malariol,  1948,  2,  115;  Patel  and  Mehta,  In- 
dian J.  Med.  Set.,  1948,  2,  675;  Khan  et  al, 
Indian  Med.  Gaz.,  1951,  86,  293).  A  dose  of  5 
or  of  7.5  mg.  per  Kg.  was  reported  to  be  insuffi- 
cient (Simeons  and  Chhatre,  Indian  Med.  Gaz., 
1947,  82,  255).  A  single  dose  of  150  mg.  intra- 
muscularly, or  150  to  300  mg.  (according  to  the 
size  of  the  patient  and  the  severity  of  the  symp- 
toms) intravenously  controlled  the  malarial  par- 
oxysm (Payne  et  al,  loc.  cit.). 

In  experimental  amebic  hepatitis  in  hamsters, 
Thompson  and  Reinertson  (Am.  J.  Trop.  Med., 
1951,  31,  707)  reported  that  Camoquin  and  chlo- 
roquine by  mouth,  and  emetine  intramuscularly, 
were  equally  effective,  whereas  carbarsone,  chlo- 
ramphenicol, chlortetracycline,  penicillin  and  di- 
hydrostreptomycin  showed  little  effect. 

Toxicology. — In  therapeutically  effective 
doses,  amodioquine  is  less  toxic  than  chloroquine 


84 


Amodiaquine    Hydrochloride 


Part   I 


(Hoekenga,  loo.  cit.).  On  a  dose  of  300  mg.  daily, 
which  is  much  larger  than  is  needed  for  therapy 
or  suppression,  weakness,  insomnia,  nausea,  vom- 
iting, diarrhea,  tenesmus,  headache,  palpitation, 
and  fainting  have  been  reported  (Berliner  et  al., 
J.  Clin.  Invest.,  1948,  27,  Suppl.,  98). 

Dose. — The  dose  is  10  mg.  of  the  base  per  Kg. 
of  body  weight  or  400  to  800  mg.  (6  to  12  grains), 
according  to  the  size  of  the  patient,  in  a  single 
dose  by  mouth  to  control  the  malarial  paroxysm 
or  as  a  weekly  suppressive  dose.  It  will  not  pre- 
vent relapse  in  P.  vivax  malaria  as  it  does  not  act 
on  the  tissue  stage  of  the  parasite.  The  dose  for 
the  infant  and  child  should  be  calculated  on  the 
basis  of  10  mg.  per  Kg.  of  body  weight.  A  dose 
of  150  to  300  mg.  may  be  given  slowly  intrave- 
nously as  a  5  per  cent  aqueous  solution.  Camoquin 
hydrochloride  is  supplied  in  tablets  representing 
200  mg.  of  the  base;  the  drug  is  included  in 
N.N.R. 

Storage. — Preserve  in  a  well-closed  container. 
LP. 

AMPHETAMINE.     B.P.,  LP. 

Amphetaminum 

C6H5.CH2.CH(NH2).CH3 

The  B.P.  defines  Amphetamine  as  (±)-2-ami- 
nopropylbenzene  and  specifies  that  it  contain  not 
less  than  98.0  per  cent  of  C9H13N.  The  LP.  indi- 
cates it  to  be  (±)-2-amino-l-phenylpropane  and 
requires  not  less  than  97.0  per  cent  of  C9H13N. 
Amphetamine  was  official  in  U.S.P.  XIV. 

Racemic  Amphetamine.  l-Phenyl-2-aminopropane.  d,l- 
Alphamethylphenethylamine.  Racemic  Desoxynorephedrine. 
Isomyn.  Benzedrine   (Smith,  Kline  &  French  Labs.). 

Amphetamine  may  be  synthesized  in  several 
ways.  One  method  starts  with  phenylacetic  acid, 
CeHsCHsCOOH,  which  is  heated  with  acetic  an- 
hydride and  sodium  acetate  to  form  methyl  benzyl 
ketone  (phenylacetone),  C6H5CH2.CO.CH3;  this 
is  heated  with  formamide,  HCONH2,  yielding  the 
formyl  derivative  of  the  ketone,  CoHsCtb.CH- 
(NHCHO).CH3,  which  on  hydrolysis  with  acid 
and  subsequent  alkalinization  yields  the  mixture 
of  racemic  bases  known  as  amphetamine.  Alter- 
natively the  methyl  benzyl  ketone  may  be  con- 
verted to  the  oxime,  which  on  reduction  yields 
amphetamine. 

Description. — Amphetamine  is  a  colorless, 
mobile  liquid,  having  a  slight  and  characteristic 
odor,  an  acrid  taste,  and  volatilizing  slowly  at 
ordinary  temperatures.  It  is  slightly  soluble  in 
water;  freely  soluble  in  alcohol,  in  ether,  and  in 
chloroform;  soluble  in  fixed  oils  and  in  volatile 
oils;  readily  soluble  in  acids.  An  aqueous  solution 
of  amphetamine  is  alkaline  to  litmus.  The  weight 
per  ml.  of  amphetamine,  at  20°,  is  between  0.930 
and  0.935  Gm.  B.P.,  LP.  Amphetamine  readily 
absorbs  carbon  dioxide  from  the  air. 

Standards  and  Tests. — Identification. — (1) 
Amphetamine  distils  at  about  200°  with  decompo- 
sition. (2)  The  benzoyl  derivative  of  ampheta- 
mine, twice  recrystallized  from  50  per  cent 
alcohol,  melts  at  about  135°.  Water. — No  turbid- 
ity is  produced  on  dissolving  1  ml.  of  ampheta- 
mine  in    10   ml.    of   anhydrous   liquid   paraffin. 


Non-volatile  matter. — Not  over  2.5  mg.  of  residue 
remains  when  500  mg.  of  amphetamine  is  heated 
on  a  water  bath  for  1  hour  and  dried  to  constant 
weight  at  105°.  Residue  on  ignition. — Not  over 
0.1  per  cent.  B.P.,  LP. 

Assay. — The  B.P.  directs  that  250  mg.  of 
amphetamine  be  dissolved  in  25  ml.  of  0.1  N 
hydrochloric  acid  and  the  excess  of  acid  titrated 
with  0.1  N  sodium  hydroxide,  using  methyl  red 
as  indicator.  Each  ml.  of  0.1  N  acid  is  equiva- 
lent to  13.52  mg.  of  C9H13N.  The  LP.  directs 
solution  of  about  250  mg.  of  amphetamine  in 
10  ml.  of  alcohol  and  direct  titration  with  0.1  N 
hydrochloric  acid,  using  methyl  red  as  indicator. 

Uses. — Amphetamine  and  its  salts  belong  to 
the  general  class  of  sympathomimetic  agents  (see 
monograph  on  this  subject  in  Part  II).  A  distinc- 
tion is  made  between  the  racemic  preparation, 
which  is  referred  to  simply  as  amphetamine,  and 
the  dextrorotatory  isomer,  called  d-amphetamine 
or  dextro-amphetamine  (Dexedrine,  Smith,  Kline 
&  French).  The  actions  of  amphetamine  are 
similar  to  those  of  ephedrine  and  methampheta- 
mine. 

Amphetamine  and  its  carbonate,  being  volatile, 
were  formerly  used  in  inhalers  to  permit  appli- 
cation of  the  vapor  to  nasal  mucosa,  thereby 
effecting  shrinkage  of  swollen  and  congested 
nasal  structures  in  head  colds,  sinusitis,  vaso- 
motor rhinitis,  and  hay  fever.  One  or  two  inhala- 
tions through  each  nostril,  at  hourly  intervals, 
was  recommended.  Simpson  and  Simon  (Am.  J. 
Pharm.,  1937,  109,  343)  found  that  ordinarily 
the  patient  would  inhale  into  the  lungs  approxi- 
mately 0.05  mg.  per  inhalation,  which  seemed  un- 
likely to  render  any  constitutional  effect.  Swine- 
ford  (/.  Allergy,  1938,  9,  572)  found,  however, 
that  it  was  possible  by  very  deep  inhalations  to 
carry  sufficient  amphetamine  into  the  bronchi  to 
cause  blanching  of  the  mucosa.  Although  unto- 
ward effects  were  infrequent  with  proper  use,  the 
convenience  and  simplicity  of  the  inhaler  facili- 
tated excessive  dosage  with  resultant  undesirable 
symptoms,  especially  in  susceptible  individuals. 
Such  overdosage  paralyzed  ciliary  action  of  the 
respiratory  mucous  membranes,  caused  abnormal 
dryness,  and  actually  aggravated  rather  than  cor- 
rected swelling  and  congestion,  with  the  possi- 
bility of  development  of  atrophic  rhinitis  (Kully, 
J.A.M.A.,  1945,  127,  307).  Restlessness  and  in- 
somnia were  the  most  frequent  untoward  effects. 
Inhalations  were  contraindicated  in  patients  with 
cardiovascular  disease  or  marked  sensitivity  to  the 
drug.  Inhalers  containing  amphetamine  were 
withdrawn  from  the  market  in  the  United  States 
because  of  their  misuse  to  produce  a  "Benzedrine 
jag"  by  soaking  the  medicated  fabric  inside  the 
inhaler  with  water  or  beverage  and  drinking  the 
solution.  Propylhexedrine  (Benzedrex)  replaced 
the  amphetamine  (Benzedrine)  in  these  inhalers. 
Oil  solutions  of  amphetamine  are  sometimes  used 
for  topical  application. 

Amphetamine  sulfate  is  administered  orally  in 
the  treatment  of  narcolepsy,  postencephalitic 
parkinsonism,  mental  depression,  alcoholism, 
obesity  and  spastic  conditions  of  the  gastrointes- 
tinal tract.  Its  pharmacology  was  reviewed  by 
Ivy  and  Krasno  (War  Med.,  1941,  1,  15). 


Part   I 


Amphetamine  85 


Cardiorespiratory  Action. — In  sufficient  dose, 
amphetamine  causes  a  marked  rise  in  the  blood 
pressure  which  comes  on  rather  slowly  and  lasts 
for  a  prolonged  time.  Beyer  (/.  Pharmacol.,  1939, 
66,  318)  found  that  33  mg.  of  the  drug  caused, 
in  humans,  an  average  rise  in  the  blood  pressure 
of  about  25  mm.  of  mercury  which  lasted  for 
more  than  seven  hours.  According  to  Tainter  et  al. 
(J.  Pharmacol.,  1936,  57,  152;  1938,  64,  190; 
1939,  66,  146),  it  does  not  dilate  the  bronchi  but 
it  has  a  depressant  effect  on  the  muscles  of  the 
gastrointestinal  tract.  Beyer  showed  that  in  man 
it  causes  a  distinct  rise  in  the  metabolic  rate 
which  lasts  for  more  than  nine  hours.  In  many 
persons  it  causes  a  loss  of  appetite,  perhaps  from 
the  delayed  emptying  of  the  stomach  (Beyer  and 
Meek,  Ann.  Int.  Med.,  1939,  63,  752).  The  most 
valuable  property  of  this  drug  is  its  stimulating 
effect  on  cerebral,  respiratory  and  vasomotor 
activity  which  exceeds  that  of  any  other  drug  of 
the  sympathomimetic  group  (Warren  and  Werner, 
/.  Pharmacol.,  1945,  85,  119).  Handley  and 
Ensberg  (Anesth.,  1945,  6,  561)  found  it  to  be 
the  most  effective  and  the  most  rapidly  acting 
stimulant  to  antagonize  respiratory  depression  due 
to  morphine;  the  other  drugs  studied  were  nik- 
ethamide, ephedrine,  pentylenetetrazol,  and  caf- 
feine. 

Central  Nervous  System  Effects. — The 
effects  of  amphetamine  and  its  salts  on  the  cere- 
brum have  led  to  its  widespread  use  in  the  treat- 
ment of  conditions  of  mental  depression,  exhaus- 
tion and  even  aberrations.  Grant  (Air  Force,  1944, 
March)  described  the  use  of  amphetamine  to 
avoid  sleepiness  in  aviators  and  this  use  of  the 
drug  by  ground  troops  was  discussed  in  Circular 
Letter  No.  58,  issued  by  the  United  States  War 
Department,  February  23,  1943.  For  mental  weari- 
ness, 5  mg.  every  3  hours  was  advised;  for  physi- 
cal fatigue,  10  mg.  every  6  hours.  The  total  dose 
should  not  exceed  30  mg.  per  week  and  adequate 
rest  must  be  obtained  at  the  end  of  each  period 
of  overexertion.  It  is  valuable  in  the  treatment 
not  only  of  acute  alcoholism  but  also  of  the  alco- 
holic psychoses  (Reifenstein  and  Davidoff, 
J. A.M. A.,  1938,  10,  1811;  Miller,  ibid.,  1942, 
120,  271).  The  effect  of  amphetamine  on  higher 
nervous  activity  in  the  human  has  been  compared 
with  that  of  alcohol  by  Finkelstein  et  al.  {Bull. 
Johns  Hopkins  Hosp.,  1945,  76,  61).  Ampheta- 
mine improved  the  response  to  conditioned  and 
unconditioned  stimuli,  whereas  alcohol  decreased 
the  response.  Amphetamine  has  been  employed 
with  more  or  less  temporary  benefit  in  the  treat- 
ment of  various  depressive  insanities  and  is  often 
of  service  in  narcolepsy  (Prinzmetal  et  al., 
J.A.M.A.,  1935,  105,  25)  and  catalepsy.  Combined 
with  amobarbital  it  is  claimed  to  moderate  ex- 
tremes of  mood  and  to  give  the  depressed  patient 
a  more  normal  outlook  and  behavior  (Grahn, 
American  Practitioner,  1950,  1,  795).  In  post- 
encephalitic parkinsonism  it  causes  not  only  im- 
provement in  the  mental  attitude  but  also  lessens 
rigidity  and  tremor.  It  is  most  effective  in  combi- 
nation with  stramonium  or  scopolamine  (Mat- 
thews, Am.  J.  Med.  Sc,  1938,  195,  448).  Myerson 
and  Loman  (Arch.  Neurol.  Psychiat.,  1942,  48, 


823)  reported  successful  treatment  of  spasmodic 
torticollis  with  amphetamine  sulfate. 

Amphetamine  sulfate  has  been  used  effectively 
in  the  treatment  of  barbiturate  poisoning  (Myer- 
son et  al.,  New  Eng.  J.  Med.,  1939,  221,  1015; 
Kornblau,  Anesth.  &  Analg.,  1948,  27,  116; 
Nabarro,  Brit.  M.  J.,  1950,  2,  924;  Dick,  Am.  J. 
Med.  Sc,  1952,  224,  281);  in  the  depression 
associated  with  the  withdrawal  of  morphine  from 
addicts  (Duckworth,  Brit.  M.  J.,  1940,  2,  628); 
for  the  exhaustion  and  lassitude  of  roentgen  ill- 
ness (Jenkinson  and  Brown,  Am.  J.  Roentgen., 
1944,  51,  496);  in  hypotension  (Peoples  and 
Guttmann,  Lancet,  1936,  1,  1107);  in  various 
combinations,  as  with  phenobarbital,  in  the  treat- 
ment of  petit  mal  epilepsy  (Livingston  and  Kajidi, 
J.A.M.A.,  1945,  129,  1071);  with  belladonna  and 
a  barbiturate  in  seasickness  (Hill,  Brit.  M.  J., 
1937,  2,  1109).  Burrill  et  al.  (J.  Dent.  Research, 
1944,  23,  337)  found  that  amphetamine  sulfate 
increased  the  analgesic  effect  of  acetophenetidin. 
Hindes  (Ind.  Med.,  1946,  15,  262)  reported  bene- 
fit in  96  per  cent  of  dysmenorrhea  cases. 

Antispasmodic  Uses. — Amphetamine  sulfate 
has  also  been  used  to  lessen  spasm  of  the  alimen- 
tary tract,  gall  bladder  or  ureters  to  facilitate 
roentgenography  of  the  intestinal  tract.  Rosen- 
berg et  al.  (J. A.M. A.,  1938,  110,  1944)  found 
that  spastic  colon  was  not  relieved.  Indeed,  its 
use  as  an  intestinal  antispasmodic  agent  is  quite 
limited,  being  overshadowed  by  its  effects  on  the 
cardiovascular  and  the  central  nervous  system. 

Use  in  Obesity. — Amphetamine  sulfate  is 
employed  for  the  reduction  of  body  weight  (Al- 
brecht,  Ann.  Int.  Med.,  1944,  21,  983;  Pelner, 
ibid.,  1945,  22,  201),  its  effect  being  due  probably 
to  a  combination  of  increased  metabolism  and 
decreased  appetite  (see  Harris  et  al.,  J. A.M. A., 
1947,  134,  1468;  Goetzl  and  Stone,  Gastro- 
enterology, 1948,  10,  1948;  Roberts,  Ann.  Int. 
Med.,  1951,  34,  1324;  Freed  and  Mizel,  ibid., 
1952,  36,  1492). 

Toxicology. — The  widespread  use  of  ampheta- 
mine sulfate  to  counteract  depression,  the  result 
of  fatigue  or  alcoholism,  is  greatly  to  be  depre- 
cated for  three  reasons:  (1)  the  tendency  toward 
habit  formation,  (2)  the  almost  certain  rise  in 
blood  pressure,  and  (3)  the  fact  that  under  some 
circumstances  not  understood  it  may  produce 
dangerous  circulatory  collapse.  Smith  (J. A.M. A., 
1939,  113,  1022)  reported  a  case  of  collapse 
terminating  fatally.  Apfelberg  (ibid.,  1938,  110, 
575),  Hertzog  and  Karlstrom  (ibid.,  1943,  121, 
256),  and  Gericke  (ibid.,  1945,  128,  1098)  also 
reported  cases  of  poisoning.  However,  the  inci- 
dence of  untoward  effects  has  been  surprisingly 
low  and  the  symptoms  of  headache,  restlessness, 
insomnia,  irritability,  palpitation  and  disturbance 
in  bowel  habit  have  usually  been  mild  and  have 
disappeared  rapidly  on  discontinuance  of  the  drug 
(Pelner,  N.  Y.  State  J.  Med.,  1944,  44,  2596). 
Daily  doses  as  large  as  30  to  50  mg.  have  been 
long  continued  without  ill  effects  (Myerson,  Am. 
J.  Med.  Sc,  1940,  199,  729)  and  Bakst  (U.  S. 
Nav.  M.  Bull.,  1944,  43,  1228)  reported  absence 
of  untoward  effects  or  withdrawal  manifestations 
after  daily  use  during  nine  years.  Shorvon  (Brit. 
M.  /.,  1945,  2,  285)  discussed  the  problem  of 


86  Amphetamine 


Part  I 


addiction  in  psychopathic  patients;  withdrawal  of 
the  drug  from  a  patient  accustomed  to  consuming 
daily  for  many  months  twenty-five  to  thirty  5  mg. 
tablets  indicated  mental  but  not  physical  depend- 
ence. Clinical  experience  has  been  that  certain 
types  of  psychopaths  can  well  tolerate  and  benefit 
from  large  doses  of  amphetamine.  In  general, 
untoward  effects  have  been  due  to  overdosage  or 
improper  dosage.  El 

Dose. — Amphetamine  base  is  used  only  by 
inhalation  (see  above) ;  its  salts  are  used  orally  or 
parenterally.  The  usual  dose  of  amphetamine  sul- 
fate is  10  mg.  (approximately  %  grain)  twice  a  day 
by  mouth,  with  a  range  of  2.5  to  10  mg.  The 
maximum  safe  dose  is  usually  20  mg.  and  the 
maximum  dose  in  24  hours  should  seldom  exceed 
100  mg.  Because  of  variation  in  individual  sus- 
ceptibility, treatment  with  amphetamine  sulfate 
should  be  started  with  a  test  dose  of  2.5  to  5  mg. 
(approximately  }4s  to  V12  grain).  To  avoid  in- 
somnia, the  drug  is  best  given  during  the  morn- 
ing and  preferably  not  later  than  midafternoon. 
The  average  doses  for  its  common  uses  are  as  fol- 
lows: depressive  states,  5  to  10  mg.  twice  daily; 
alcoholism,  5  to  15  mg.  twice  daily;  postencepha- 
litic parkinsonism,  10  to  20  mg.  twice  daily; 
narcolepsy,  10  to  40  mg.  two  or  three  times  daily 
as  required;  obesity,  2.5  to  5  mg.  twice  daily 
about  one-half  hour  before  meals.  In  barbiturate 
poisoning,  the  initial  dose  is  20  to  50  mg.  intra- 
venously in  a  2  per  cent  solution;  subsequently 
50  to  100  mg.  may  be  given  intramuscularly,  every 
hour  if  necessary,  to  counteract  the  hypnosis  and 
depression  of  the  central  nervous  system. 

AMPHETAMINE  PHOSPHATE.     N.F. 

Racemic  Amphetamine  Phosphate,  rf/-Monobasic 
Amphetamine  Phosphate,  d/-Amphetaminium  Phosphate 

C9H13N.H3PO4 

"Amphetamine  Phosphate,  dried  at  105°  for  2 
hours,  contains  not  less  than  98  per  cent  of 
C9H13N.H3PO4."  N.F. 

Profetamine  Phosphate  (Clark  &  Clark) ;  Raphetamine 
Phosphate  (Strasenburgh) . 

This  salt  differs  from  amphetamine  sulfate  in 
being  a  salt  of  phosphoric  acid  in  which  one  of 
the  three  hydrogen  atoms  of  the  latter  is  neu- 
tralized by  amphetamine  base. 

Description. — "Amphetamine  Phosphate  oc- 
curs as  a  white,  odorless,  crystalline  powder.  It 
has  a  bitter  taste.  Amphetamine  Phosphate  i» 
freely  soluble  in  water,  and  slightly  soluble  in  alco- 
hol. It  is  practically  insoluble  in  benzene,  in  chloro- 
form, and  in  ether.  The  pH  of  a  solution  of 
Amphetamine  Phosphate  (1  in  20)  is  between 
4  and  5."  N.F. 

The  standards,  tests  and  assay  are  identical 
with  those  for  amphetamine  sulfate,  except  for 
the  difference  in  the  identification  of  the  cation; 
also,  the  residue  on  ignition  of  amphetamine  phos- 
phate is  0.1  per  cent. 

Uses. — Amphetamine  phosphate  is  used  for 
the  same  purposes  as  amphetamine  sulfate.  Be- 
cause of  the  lower  content  of  amphetamine  base 
in  the  phosphate,  as  compared  with  the  sulfate,  it 
may  be  calculated  that  12.6  mg.  of  the  phosphate 
is  equivalent  to   10  mg.  of  the  sulfate,  so  that 


doses  of  amphetamine  phosphate  would  have  to 
be  approximately  25  per  cent  greater  than  those 
of  amphetamine  sulfate  for  equivalent  effect.  For 
most  purposes,  however,  amphetamine  phosphate 
is  actually  used  in  the  same  dose  as  amphetamine 
sulfate.  As  an  analeptic  amphetamine  phosphate 
is  administered  intravenously  or  intramuscularly 
in  doses  of  20  to  50  mg.  every  30  to  60  minutes 
until  consciousness  is  restored;  the  solution  em- 
ployed commonly  contains  10  mg.  per  ml.  and  is 
preserved  with  0.5  per  cent  chlorobutanol.  The 
N.F.  gives  the  usual  dose  as  5  mg. 

Storage. — Preserve  "in  well-closed  contain- 
ers." N.F. 

AMPHETAMINE  PHOSPHATE 
INJECTION.     N.F. 

"Amphetamine  Phosphate  Injection  is  a  sterile 
solution  of  amphetamine  phosphate  in  water  for 
injection.  It  contains  not  less  than  95  per  cent 
and  not  more  than  105  per  cent  of  the  labeled 
amount  of  C9H13N.H3PO4."  N.F. 

Storage. — Preserve  "in  single-dose  or  mul- 
tiple-dose containers,  preferably  of  Type  I  glass." 
N.F. 

Usual  Size. — 100  mg.  in  10  ml. 

AMPHETAMINE  PHOSPHATE 
TABLETS.     N.F. 

"Amphetamine  Phosphate  Tablets  contain  not 
less  than  90  per  cent  and  not  more  than  110  per 
cent  of  the  labeled  amount  of  C9H13N.H3PO4." 
N.F. 

Usual  Size. — 5  mg.  (approximately  Vn  grain). 

DIBASIC  AMPHETAMINE 
PHOSPHATE.    N.F. 

Racemic  Dibasic  Amphetamine  Phosphate,  rf/Dibasic 

Amphetamine  Phosphate,  ^'/-Dibasic  Amphetaminium 

Phosphate 

(C9Hi3N)2.H3P04 

"Dibasic  Amphetamine  Phosphate,  dried  at 
105°  for  2  hours,  contains  not  less  than  98  per 
cent  of  (C9H13N)2.H3P04."  N.F. 

This  salt  differs  from  amphetamine  phosphate 
in  that  two  of  the  hydrogen  atoms  of  phosphoric 
acid  are  neutralized  by  amphetamine  base. 

Description. — "Dibasic  Amphetamine  Phos- 
phate occurs  as  a  white,  odorless,  crystalline  pow- 
der. It  has  a  slightly  bitter  taste.  One  Gm.  of 
Dibasic  Amphetamine  Phosphate  dissolves  in 
about  20  ml.  of  water,  and  in  about  650  ml.  of 
alcohol.  It  is  insoluble  in  ether.  The  pH  of  a  solu- 
tion of  Dibasic  Amphetamine  Phosphate  (1  in 
20)  is  between  7  and  8.5."  N.F. 

Uses. — This  salt  differs  from  amphetamine 
phosphate  in  containing  approximately  25  per 
cent  more  of  amphetamine  base  and  thus  it  is 
equivalent  to  amphetamine  sulfate  when  equal 
weights  of  the  two  are  compared.  Dibasic  am- 
phetamine phosphate  is  neutral  in  aqueous  solu- 
tion, while  the  monobasic  phosphate  is  acid;  this 
difference,  however,  is  of  no  significance  in  the 
use  of  the  two  salts.  The  dose  of  dibasic  ampheta- 
mine phosphate  is  exactly  the  same  as  that  of 
amphetamine  sulfate.  The  N.F.  gives  the  usual 
dose  as  5  mg. 


Part  I 


Amphetamine  Sulfate  87 


Storage. — Preserve  "in  well-closed  containers." 
N.F. 

DIBASIC  AMPHETAMINE 
PHOSPHATE  TABLETS.     N.F. 

"Dibasic  Amphetamine  Phosphate  Tablets  con- 
tain not  less  than  90  per  cent  and  not  more 
than  110  per  cent  of  the  labeled  amount  of 
(C9Hi3N)2.H3P04."  N.F. 

Usual  Size. — 5  mg.  (approximately  Yi2  grain). 

DEXTRO-AMPHETAMINE 
PHOSPHATE.     N.F. 

Monobasic  Dextro-amphetamine  Phosphate,  Dextro- 
amphetaminium  Phosphate 

C9H13N.H3PO4 

"Dextro-amphetamine  Phosphate,  dried  at  105° 
for  2  hours,  contains  not  less  than  98.5  per  cent  of 
C9H13N.H3PO4."  N.F. 

This  salt  has  the  same  relationship  to  ampheta- 
mine phosphate  as  dextro-amphetamine  sulfate 
has  to  amphetamine  sulfate. 

Description. — "Dextro-amphetamine  Phos- 
phate occurs  as  a  white,  odorless,  crystalline  pow- 
der. It  has  a  bitter  taste.  One  Gm.  of  Dextro- 
amphetamine Phosphate  dissolves  in  20  ml.  of 
water.  It  is  slightly  soluble  in  alcohol  and  is  prac- 
tically insoluble  in  benzene,  in  chloroform,  and  in 
ether.  The  pH  of  a  solution  of  Dextro-ampheta- 
mine Phosphate  (1  in  10)  is  between  4  and  5." 
N.F. 

Uses. — Dextro-amphetamine  phosphate  has  the 
same  actions  and  uses  as  amphetamine  sulfate 
but,  as  with  the  dextro  form  of  amphetamine 
sulfate,  the  dextro  isomer  of  amphetamine  phos- 
phate is  about  twice  as  active  in  its  central  stimu- 
lant effects  as  the  racemic  form  of  amphetamine 
phosphate.  Accordingly  the  usual  dose  of  the  dex- 
tro isomer  should  be  about  half  that  of  racemic 
monobasic  amphetamine  phosphate;  however,  the 
N.F.  gives  the  usual  dose  as  5  mg. 

Storage. — Preserve  "in  well-closed  containers." 
N.F. 

DEXTRO-AMPHETAMINE 
PHOSPHATE  TABLETS.  N.F. 

"Dextro-amphetamine  Phosphate  Tablets  con- 
tain not  less  than  90  per  cent  and  not  more 
than  110  per  cent  of  the  labeled  amount  of 
C9H13N.H3PO4."  N.F. 

Usual  Size. — 5  mg. 

DIBASIC  DEXTRO-AMPHETAMINE 
PHOSPHATE.     N.F. 

Dibasic  Dextro-amphetaminium  Phosphate 

(C9Hi3N)2.H3P04 

"Dibasic  Dextro-amphetamine  Phosphate,  dried 
at  105°  for  2  hours,  contains  not  less  than  98  per 
cent  of  (C9Hi3N)2.H3P04."  N.F. 

This  salt  corresponds  to  the  dextro  isomer  of 
amphetamine  sulfate  in  containing,  by  a  coinci- 
dence of  molecular  weights,  the  same  proportion 
of  amphetamine.  It  differs  from  dextro-ampheta- 
mine phosphate  in  that  two  of  the  hydrogen 
atoms  of  phosphoric  acid  are  neutralized  by  am- 


phetamine, thereby  making  the  salt  less  acid  than 
dextro-amphetamine  phosphate. 

Description. — "Dibasic  Dextro-amphetamine 
Phosphate  occurs  as  a  white,  odorless,  crystalline 
powder.  It  has  a  slightly  bitter  taste.  One  Gm.  of 
Dibasic  Dextro-amphetamine  Phosphate  dissolves 
in  about  20  ml.  of  water,  and  in  about  650  ml.  of 
alcohol.  It  is  insoluble  in  ether.  The  pH  of  a  solu- 
tion of  Dibasic  Dextro-amphetamine  Phosphate 
(1  in  20)  is  between  6.0  and  7.5."  N.F. 

Uses. — The  uses  of  this  dextro  isomer  are 
qualitatively  the  same  as  amphetamine  sulfate; 
the  dose  is  theoretically  and  actually  the  same  as 
for  dextro-amphetamine  sulfate,  since  both  dextro 
salts  contain  the  same  proportion  of  active  base. 
The  N.F.  gives  the  usual  dose  as  5  mg. 

Storage. — Preserve  "in  well-closed  containers." 
N.F. 

DIBASIC   DEXTRO-AMPHETAMINE 
PHOSPHATE  TABLETS.     N.F. 

"Dibasic  Dextro-amphetamine  Phosphate  Tab- 
lets contain  not  less  than  90  per  cent  and  not 
more  than  110  per  cent  of  the  labeled  amount  of 
(C9Hi3N)2.H3P04."  N.F. 

Usual  Size. — 5  mg. 

AMPHETAMINE  SULFATE. 
U.S.P.,  B.P.,  LP. 

Amphetaminium  Sulfate,  d/-l-Phenyl-2-aminopropane 
Sulfate,   [Amphetaminae  Sulfas] 


ch,chch,    so; 

NH3 

"Amphetamine  Sulfate,  dried  at  105°  for  2 
hours,  contains  not  less  than  98  per  cent  and  not 
more  than  100.5  per  cent  of  (C9Hi3N)2.H.2S04." 
U.S. P.  The  B.P.  defines  Amphetamine  Sulphate  as 
(±)-2-aminopropylbenzene  sulfate,  and  requires 
not  less  than  99.0  per  cent  of  (CgHi3N)2.H2S04, 
calculated  with  reference  to  the  substance  dried 
to  constant  weight  at  105°.  The  LP.  defines  it  as 
(±)-2-amino-l-phenylpropane  sulfate,  and  re- 
quires not  less  than  98.0  per  cent  of  (CgHi3N)2.- 
H2SO4,  the  substance  not  being  dried  prior  to 
assay. 

B.P.  Amphetamine  Sulphate.  LP.  Amphetamini  Sulfas. 
Racemic  Amphetamine  Sulfate.  d/-a-Methylphenethylamine 
Sulfate.  Benzedrine  Sulfate  (Smith,  Kline  &  French  Labs.). 

The  B.P.  states  that  this  salt  may  be  prepared 
by  neutralizing  an  alcoholic  solution  of  ampheta- 
mine base  with  sulfuric  acid. 

Description. — "Amphetamine  Sulfate  occurs 
as  a  white,  odorless,  crystalline  powder.  It  has  a 
slightly  bitter  taste.  Its  solutions  are  acid  to 
litmus,  having  a  pH  of  5  to  6.  One  Gm.  of 
Amphetamine  Sulfate  dissolves  in  about  9  ml.  of 
water,  and  in  about  500  ml.  of  alcohol.  It  is  in- 
soluble in  ether."  U.S.P. 

Standards  and  Tests. — Identification. — (1) 
The  benzoyl  derivative  of  amphetamine  melts  be- 
tween 131°  and  135°.  (2)  A  solution  of  ampheta- 
mine sulfate  responds  to  tests  for  sulfate.  Water. 
— Not  over  1  per  cent  when  dried  at  105°  for 
2  hours.  Residue  on  ignition. — Not  over  0.2  per 


88  Amphetamine  Sulfate 


Part   I 


cent.  Dextroamphetamine. — A  1  in  SO  solution 
of  amphetamine  sulfate  is  optically  inactive. 
U.S.P. 

Assay. — A  sample  of  300  mg.  of  dried  am- 
phetamine sulfate  is  dissolved  in  water,  made 
alkaline  with  sodium  hydroxide,  and  the  ampheta- 
mine base  extracted  with  ether.  The  ether  is 
evaporated  to  a  volume  of  about  10  ml.,  20  ml. 
of  0.1  N  sulfuric  acid  is  added  and.  after  evapo- 
ration of  the  remainder  of  the  ether,  the  excess 
of  acid  is  titrated  with  0.1  A*  sodium  hydroxide, 
using  methyl  red  T.S.  as  indicator.  Each  ml.  of 
0.1  A7  sulfuric  acid  represents  18.43  mg.  of 
(C9Hi3N)2.H2S04.  U.S.P. 

For  uses  and  dose  of  amphetamine  sulfate  see 
under  Amphetamine,  [v] 

Storage. — Preserve  "in  well-closed  contain- 
ers." U.S.P. 

AMPHETAMINE  SULFATE 
TABLETS.     U.S.P.  (LP.) 

"Amphetamine  Sulfate  Tablets  contain  not  less 
ihan  90  per  cent  and  not  more  than  110  per  cent 
of  the  labeled  amount  of  (C9Hi3N)2.H2S04." 
U.S.P.  The  corresponding  LP.  limits  are  92.0  to 
108.0  per  cent. 

LP.  Tablets  of  Amphetamine  Sulfate;  Compressi  Am- 
pbetamini  Sulfatis. 

Usual  Sizes. — 5  and  10  mg. 

DEXTRO  AMPHETAMINE 
SULFATE.     U.S.P. 

d-Amphetaminium  Sulfate,  d-l-Phenyl-2-amino- 
propane  Sulfate 

"Dextro  Amphetamine  Sulfate,  the  dextrorota- 
tory isomer  of  amphetamine  sulfate,  dried  at  105° 
for  2  hours,  contains  not  less  than  98  per  cent  and 
not  more  than  100.5  per  cent  of  (C9Hi3N)2.- 
H2SO4."  U.S.P. 

Dexedrine  Sulfate   (.Smith,  Kline  &  French  Labs.). 

Dextro  amphetamine  sulfate  is  obtained  by 
resolution  of  the  racemic  variety,  which  is  official 
as  Amphetamine  Sulfate. 

Description. — "Dextro  Amphetamine  Sulfate 
occurs  as  a  white,  odorless,  crystalline  powder. 
Its  1  in  20  solution  is  acid  to  litmus,  having  a  pH 
of  5  to  6.3.  One  Gm.  of  Dextro  Amphetamine 
Sulfate  dissolves  in  about  10  ml.  of  water  and  in 
about  800  ml.  of  alcohol.  It  is  insoluble  in  ether." 
U.S.P. 

Standards  and  Tests. — Identification. — (1) 
The  benzoyl  derivative  melts  between  155°  and 
158°.  (2)  A  1  in  10  solution  of  dextro  amphet- 
amine sulfate  responds  to  tests  for  sulfate.  Spe- 
cific rotation. — Not  less  than  +20°  and  not  more 
than  +23. 5°,  when  determined  in  a  solution  con- 
taining 400  mg.  of  dried  dextro  amphetamine  sul- 
fate in  each  10  ml.  Loss  on  drying. — Not  over 
1  per  cent,  when  dried  at  105°  for  2  hours.  Resi- 
due on  ignition. — Not  over  0.1  per  cent.  U.S.P. 

Assay. — The  assay  is  performed  as  described 
under  Amphetamine  Sulfate.  U.S.P. 

Uses. — The  dextrorotatory  form  of  amphet- 
amine was  observed  bv  Prinzmetal  and  Alles 
(Proc.  S.  Exp.  Bio.  Med.,  1939,  42,  206)  to  have 
a  substantially  greater  central  nervous  stimulating 


effect  than  the  racemic  form;  also,  the  levorota- 
tory  form  was  found  to  be  relatively  devoid  of 
this  euphoriant  action.  Otherwise  the  actions  of 
the  optically  active  and  racemic  forms  of  the 
compound  are  pharmacodynamically  similar.  The 
general  clinical  pharmacology  of  amphetamine 
has  been  discussed  in  the  monograph  on  Amphet- 
amine; for  further  information  see  Reifenstein 
and  Davidoff  (N.  Y.  State  J.  Med.,  1939,  39,  42). 
Confirming  the  initial  observations  of  Prinzmetal 
and  Alles,  Davidoff  (Med.  Rec,  1943,  156,  422) 
reported  racemic  amphetamine  to  be  distinctly 
weaker  in  its  stimulation  of  motor  and  intellectual 
function  than  either  d-amphetamine  or  desoxy- 
ephedrine  (methamphetamine).  Similarly,  Novelli 
and  Tainter  (/.  Pharmacol.,  1943,  77,  325)  re- 
ported that  dextro  amphetamine  was  at  least  twice 
as  active  as  the  racemic  form  in  its  effects  on  the 
motor  activity  of  rats.  This  effect  on  the  sensorium 
and  motor  phenomena  is  attributable  to  an  inher- 
ent activity  of  the  compound  which  is  unique, 
for  usually  the  levo-form  of  biologically  active 
agents  having  one  asymmetric  carbon  atom  is 
more  active  than  the  dextro  form. 

Beyer  and  Skinner  (ibid.,  1940,  68,  419)  stud- 
ied the  detoxication  and  excretion  of  racemic 
amphetamine  and  its  optically  active  forms  in 
man.  They  found  essentially  no  difference  in  the 
absorption  and  excretion  of  the  three  forms,  al- 
though the  greater  effect  of  the  dextro  form  on 
the  sensorium  was  quite  evident.  Thus,  up  to  64 
per  cent  of  either  active  form  of  amphetamine 
was  excreted  during  a  period  of  24  hours. 

As  a  generalization,  dextro  amphetamine  tends 
to  be  used  in  place  of  the  racemic  form  in  those 
conditions  where  stimulation  of  the  sensorium  is 
indicated,  as  in  certain  depressive  states,  in  post- 
encephalitic parkinsonism,  and  in  narcolepsy.  In 
a  study  of  comparative  therapeutic  effects  of  the 
two  forms  on  humans,  Freed  (West.  J.  Surg. 
Obst.  Gyn.,  1949,  57,  67)  found  the  racemic  salt 
to  be  equal,  in  appetite-curbing  effect,  to  the 
dextro  salt  when  the  latter  is  used  in  half  the 
dose  of  the  former.  He  received  the  clinical  im- 
pression that  the  individual  who  requires  large 
doses  of  most  drugs  for  a  therapeutic  effect  re- 
sponds more  satisfactorily  to  racemic  amphet- 
amine sulfate  than  to  the  dextro  isomer;  the  high- 
strung,  hypersensitive  individual  who  is  prone  to 
drug  intolerance  and  who  responds  to  small  doses 
of  drugs  in  general  seems  to  prefer  the  dextro 
isomer.  In  anhedonic  individuals  the  levo  form 
of  amphetamine,  which  is  present  in  the  racemic 
drug,  produces  through  its  stronger  adrenergic 
action  a  satiation  to  food  at  lower  dosage  levels; 
the  hypersensitive  individual,  on  the  other  hand, 
does  not  tolerate  too  well  the  adrenergic  effect  of 
the  levo  isomer  and  therefore  prefers  dextro 
amphetamine  sulfate. 

Toxicology. — The  undesirable  effects  of  the 
drug  following  overdosage  are  excessive  excite- 
ment, loquaciousness,  headache  and  insomnia,  as 
observed  also  with  racemic  amphetamine.  Since 
the  drug  is  slowly  excreted  and  metabolized  these 
effects  may  persist  for  24  to  48  hours  when  the 
dose  is  excessive.  According  to  Freed  (loc.  cit.) 
there  is  considerably  less  incidence  of  side  reac- 
tions with  dextro  amphetamine  sulfate  than  with 


Part  I 


Amyl   Nitrite  89 


the  racemic  salt.  Since  the  peripheral  vascular 
action  of  the  dextro  and  racemic  salts  is  believed 
to  be  quantitatively  the  same,  it  is  apparent  that 
the  lower  dosage  required  in  the  case  of  the  dextro 
compound  is  less  likely  to  elicit  peripheral  vascu- 
lar complications.  Dextro  amphetamine  sulfate  is 
usually  not  indicated  in  cases  of  severe  hyper- 
tension, angina  pectoris,  hyperthyroidism,  and 
Raynaud's  disease. 

Dose. — The  usual  adult  dose  of  dextro  amphet- 
amine sulfate  in  simple  depressed  states,  obesity, 
alcoholism,  hyperemesis  gravidarum,  or  drowsi- 
ness is  5  mg.  twice  a  day,  with  a  range  of  dose 
of  2.5  to  5  mg.  The  last  dose  should  precede  the 
anticipated  bedtime  by  at  least  4  hours;  other- 
wise, the  stimulating  effect  of  the  drug  will  inter- 
fere with  sleep,  in  which  case  it  may  be  necessary 
to  counteract  the  effect  with  barbiturate  hypnotics. 
The  dose  for  control  of  narcolepsy  or  the  depres- 
sion of  parkinsonism  may  be  25  mg.  a  day  or 
more,  symptomatically.  The  maximum  safe  dose 
in  24  hours  seldom  exceeds  50  mg.  Dexedrine 
Sulfate  Spanstdes  contain  15  mg.  of  the  dextro 
salt  in  the  form  of  tiny  pellets,  of  which  there 
are  over  a  hundred  in  each  capsule,  having  vary- 
ing disintegration  times  so  as  to  release  the  drug 
uniformly  over  a  period  of  8  to  10  hours;  for  use 
in  weight  reduction  one  such  capsule,  taken  in 
the  morning,  curbs  appetite  throughout  the  day. 

Storage. — Preserve  "in  well-closed  containers." 
U.S.P. 

DEXTRO  AMPHETAMINE  SULFATE 
TABLETS.     U.S.P. 

"Dextro  Amphetamine  Sulfate  Tablets  contain 
not  less  than  90  per  cent  and  not  more  than  110 
per  cent  of  the  labeled  amount  of  (C,9Hi3N)2.H2- 
S04."  U.S.P. 

Usual  Sizes. — 5  and  10  mg. 

AMYL  NITRITE.     U.S.P.,  B.P.,  LP. 

Isoamyl  Nitrite,  [Amylis  Nitris] 

CH3.CH(CH3)  .CH2.CH2.ONO 

"Amyl  Nitrite  contains  not  less  than  90  per 
cent  of  C5H11NO2.  Caution. — Amyl  Nitrite  is 
very  flammable.  Do  not  use  where  it  may  be 
ignited."  U.S.P. 

The  B.P.  states  that  Amyl  Nitrite  consists 
chiefly  of  the  nitrites  of  3-methylbutanol,  (013)2- 
CH.CH2.CH2.OH,  and  2-methylbutanol,  (C2H5) 
(CH3)CH.CH2.0H;  it  is  required  to  contain  not 
less  than  90.0  per  cent  w/w  of  nitrites,  calculated 
as  CsHuCteN.  The  LP.  indicates  it  to  be  a  mix- 
ture of  the  nitrite  of  3-methylbutanol- 1  with  a 
small  quantity  of  the  nitrite  of  2-methylbutanol-l 
and  other  nitrites  of  the  homologous  series;  the 
purity  rubric  is  the  same  as  that  of  the  U.S.P. 
and  B.P. 

Araylium  Nitrosum;  Nitris  Amylicus.  Ft.  Azotite  d'amyle. 
Ger.  Amylnitrit;  Salpetrigsaureamylester.  It.  Nitrito 
d'amile;  Nitrito  d'isoamile.  Sp.  Nitrito  de  amilo;  Ester 
isoamilnitroso. 

This  substance,  discovered  by  Balard  in  1844, 
is  the  product  of  esterifi cation  of  amyl  alcohol 
and  nitrous  acid.  A  convenient  method  for  pre- 
paring the  ester  by  the  interaction  of  amyl  alcohol, 


sulfuric  acid  and  sodium  nitrite  is  described  by 
Noyes  (J.A.C.S.,  1933,  55,  3888).  Other  methods 
of  preparation  are  described  in  the  U.S.D.,  20th 
ed.,  p.  140. 

The  amyl  alcohol  used  in  the  preparation  of 
amyl  nitrite  is  frequently  a  mixture  of  isomeric 
alcohols;  as  a  result,  the  product  may  likewise 
be  a  mixture  of  two  or  more  isomers.  Usually, 
it  consists  chiefly  of  isoamyl  nitrite, 

CH3.CH  ( CH3)  .CH2.CH2.ONO 

with  smaller  proportions  of  optically  active,  sec- 
ondary and  amyl  nitrite,  CH3.CH2.CH(CH3).- 
CH2.ONO.  Read  et  al.  {Chinese  J.  Physiol,  1933, 
7,  253)  made  comparative  physiological  studies 
of  the  effects  of  the  various  isomeric  amyl  nitrites; 
they  found  that  all  act  qualitatively  alike  but  be- 
lieve that  the  tertiary  amyl  nitrite  is  the  most 
valuable  from  the  standpoint  of  practical  thera- 
peutics. 

Description. — "Amyl  Nitrite  is  a  clear,  yel- 
lowish liquid,  having  a  peculiar,  ethereal,  fruity 
odor.  It  is  volatile  even  at  low  temperatures  and 
is  flammable.  Amyl  Nitrite  is  almost  insoluble  in 
water,  but  is  miscible  with  alcohol  and  with  ether. 
The  specific  gravity  of  Amyl  Nitrite  is  not  less 
than  0.865  and  not  more  than  0.875."  U.S.P. 

Standards  and  Tests. — Identification. — (1) 
Amyl  valerate,  recognizable  by  its  odor,  is  pro- 
duced when  a  mixture  of  2  ml.  of  sulfuric  acid,  2 
drops  of  amyl  nitrite  and  2  drops  of  water  is  di- 
luted with  water.  (2)  A  greenish  brown  color  is 
produced  on  adding  a  few  drop  of  amyl  nitrite  to 
a  mixture  of  1  ml.  of  ferrous  sulfate  T.S.  and  5 
ml.  of  diluted  hydrochloric  acid.  Acidity. — The 
red  tint  of  a  mixture  of  1  ml.  of  normal  sodium 
hydroxide,  10  ml.  of  water  and  1  drop  of  phenol- 
phthalein  T.S.  is  not  discharged  by  5  ml.  of  amyl 
nitrite  when  the  glass-stoppered  cylinder  used  as 
a  container  is  inverted  three  times.  Aldehyde. — 
No  brown  or  black  color  is  developed  on  mixing, 
successively,  1.5  ml.  of  silver  nitrate  T.S.,  1.5  ml. 
of  aldehyde-free  alcohol,  enough  ammonia  T.S.  to 
redissolve  the  precipitate  which  forms,  and  1  ml. 
of  amyl  nitrite,  the  mixture  being  heated  gently 
for  1  minute.  U.S.P. 

The  B.P.  specifies  that  not  less  than  85  per  cent 
shall  distil  between  90°  and  100°.  The  residue  on 
evaporation  is  not  more  than  0.01  per  cent  w/v. 
A  test  for  aldehyde,  based  on  the  color  produced 
with  sodium  hydroxide,  is  also  given. 

Assay. — A  3-ml.  sample  of  amyl  nitrite  is 
weighed  in  alcohol  and  the  solution  diluted  to  100 
ml.  A  10-ml.  portion  of  this  solution  is  assayed 
gasometrically,  by  the  method  described  under 
Ethyl  Nitrite  Spirit.  U.S.P. 

The  B.P.  assay  is  practically  the  same  as  that 
of  the  U.S.P.  The  LP.  assay  is  based  on  the  re- 
duction of  potassium  chlorate  by  the  nitrite  to 
potassium  chloride,  the  amount  of  the  latter  being 
determined  by  precipitation  with  a  measured  ex- 
cess of  0.1  A7  silver  nitrate,  followed  by  titration 
of  the  excess  silver  nitrate  with  0.1  N  ammonium 
thiocyanate,  with  the  silver  chloride  being  re- 
moved by  filtration.  Since  three  molecules  of  amyl 
nitrite  are  required  to  reduce  one  molecule  of 
potassium  chlorate  to  chloride,  the  equivalent 
weight  of  amyl  nitrite  is  three  times  its  molecular 


90  Amyl   Nitrite 


Part  I 


weight.  Each  ml.  of  0.1  N  silver  nitrate  repre- 
sents 35.1  mg.  of  C5H11O2N.  LP. 

Uses. — Physiologically,  amyl  nitrite  acts  like 
sodium  nitrite  (g.  v.),  except  that  it  is  much 
quicker  and  more  evanescent,  its  effect  appearing 
in  about  30  seconds  and  lasting  for  only  about  3 
minutes.  Amyl  nitrite  is  used  in  medicine  for 
three  purposes:  To  relax  spasms  in  the  arteries, 
to  control  convulsions,  and  for  the  relief  of  the 
asthmatic  paroxysm.  It  is  of  service  only  where 
an  immediate,  transient  effect  is  desired. 

Cardiac. — In  angina  pectoris  it  improves  cir- 
culation in  the  coronary  arteries,  even  though  a 
drop  in  blood  pressure  occurs.  Since  the  duration 
of  angina  attacks  is  less  than  3  minutes  in  the 
majority  of  cases  (Riseman  and  Brown,  New 
Eng.  J.  Med.,  1937,  217,  470)  only  the  rapidly 
acting  substances,  amyl  nitrite  or  nitroglycerin, 
are  effective.  The  pain  due  to  demonstrable  (elec- 
trocardiogram or  gross  pathology)  myocardial 
infarction  is  usually  not  benefited  by  nitrites; 
since  such  patients  often  manifest  peripheral  cir- 
culatory collapse,  nitrites  must  be  employed  with 
great  caution.  Goldberger  {Am.  Heart  J.,  1945, 
30,  60)  made  electrocardiograms  following  amyl 
nitrite  inhalation  by  patients  with  hypertension 
and  enlargement  of  the  heart;  most  of  these  pa- 
tients showed  a  change  of  the  T  wave  from  nega- 
tive to  positive  for  3  to  4  minutes.  Gross  {Am. 
Heart  J .,  1945,  30,  19)  reported  on  the  use  of 
the  time  between  the  first  inhalation  of  amyl 
nitrite  and  the  appearance  of  a  definite  heat  sensa- 
tion in  the  face  as  a  measurement  of  lung-to-face 
circulation  time;  in  normal  persons  the  time 
ranged  from  14  to  25  seconds;  in  congestive  heart 
failure  the  time  varied  from  31  to  54  seconds;  in 
emphysematous  patients  it  was  normal.  In  a  study 
of  the  effect  of  several  drugs  on  the  pressure  in 
the  pulmonary  artery  of  unanesthetized  dogs 
(/.  Pharmacol.,  1943,  77,  80),  amyl  nitrite  is  re- 
ported to  have  no  effect.  In  such  dogs,  Stephens 
(/.  Physiol,  1940,  99,  127)  found  that  amyl 
nitrite  caused  contraction  of  the  spleen. 

Cerebral. — In  convulsive  disorders,  amyl  ni- 
trite is  of  service  only  when  it  is  necessary  to 
cause  immediate  relaxation;  thus  in  tetanus,  be- 
cause of  the  duration  of  the  convulsive  tendency, 
the  fugaciousness  of  its  action  renders  it  of  rela- 
tively small  service ;  on  the  other  hand,  in  strych- 
nine poisoning,  by  restraining  the  convulsions  long 
enough  for  more  durable  motor  depressants  to 
act,  it  may  prove  a  life-saving  remedy.  In  ordi- 
nary epilepsy  it  is  of  little  service,  but  in  status 
epilepticus,  in  which  the  patient  passes  from  one 
convulsion  to  another,  the  drug  may  be  of  great 
benefit.  Again,  in  those  occasional  cases  of  epi- 
lepsy in  which  the  seizure  is  preceded  by  an  aura 
of  sufficient  length,  inhalation  of  amyl  nitrite  as 
soon  as  the  aura  commences  may  abort  the 
paroxysm.  Brief  cessation  of  the  tremors  in 
Parkinson's  disease  following  inhalation  of  amyl 
nitrite  has  been  reported  by  Garai  {Arch.  Neurol. 
Psychiat.,  1951,  65,  452). 

Pulmonary. — In  many  cases  of  asthma  it  will 
cause  an  immediate,  if  only  temporary,  cessation 
of  the  paroxysm.  Epinephrine  and  aminophylline 
are  usually  more  effective.  The  claim  of  Hare  that 
"amyl  nitrite  is  of  great  value  for  the  relief  of 


hemoptysis  has  been  confirmed  by  a  number  of 
observers  (see  Brit.  M.  L,  July  15,  1911J.  Its 
action  in  this  condition  is  probably  the  result  of 
dilatation  of  the  splanchnic  blood  vessels. 

Colic. — Although  the  short-acting  nitrites  are 
of  little  value  in  most  spasms  of  the  gastrointes- 
tinal tract,  they  may  be  effective  in  lead  colic 
{Arch.  Int.  Med.,  1932,  49,  270)  and  may  aid  in 
the  differentiation  between  spasm  and  organic 
lesions  during  x-ray  examinations.  These  drugs  are 
often  beneficial  in  the  relief  of  biliary  colic  {Surg., 
Gynec.  Obst.,  1936,  63,  451)  both  before  and 
after  cholecystectomy,  including  instances  of 
biliary  dyskinesia.  Amyl  nitrite  is  also  indicated 
in  the  treatment  of  renal  colic  {Arch.  urug.  de 
med.,  1944,  24,  105).  Prytz  (Ugeskr.  f.  laeger, 
1949,  111,  426)  described  its  use,  by  inhalation, 
in  obstetrics  for  the  relief  of  constriction  ring 
dystocia  (BandFs  contraction  ring).  It  is  also 
valuable  in  some  cases  of  migraine  (see  Nicotinic 
Acid).  In  the  management  of  cyanide  poisoning, 
amyl  nitrite  plays  an  important  role  (see  Diluted 
Hydrocyanic  Acid). 

Amyl  nitrite  is  generally  administered  by  in- 
halation, usually  in  doses  of  from  three  to  five 
drops,  although  much  larger  quantities  have  been 
given.  The  initial  dose  should  be  three  drops  on 
a  handkerchief  held  close  to  the  nose,  the  dose 
being  gradually  increased  pro  re  nata.  The  hand- 
kerchief should  be  withdrawn  as  soon  as  the  face 
flushes  or  severe  palpitation  is  noted,  as  the  effects 
increase  for  some  time  after  inhalation  is  discon- 
tinued. The  best  method,  however,  of  administer- 
ing the  very  volatile  liquid  is  by  the  use  of  glass 
pearls — small  flask-shaped  vessels  containing  the 
nitrite;  these  are  crushed  in  a  handkerchief  or 
towel  when  wanted  for  inhalation,  the  thin  and 
fragile  glass  causing  no  inconvenience.  The  drug 
may  also  be  given  by  mouth. 

Toxicology. — "When  inhaled  in  doses  of  from 
five  to  ten  drops,  amyl  nitrite  produces  in  man 
violent  flushing  of  the  face,  accompanied  by  a 
feeling  as  though  the  head  would  burst,  and  a  very 
excessive  action  of  the  heart.  Along  with  these 
symptoms,  after  a  larger  quantity,  there  is  a  sense 
of  suffocation,  and  more  or  less  marked  muscular 
weakness.  Since  amyl  nitrite  increases  intraocular 
tension,  it  must  be  used  with  caution  in  patients 
with  glaucoma.  In  addition  to  the  headache  which 
it  causes,  it  increases  the  pressure  of  the  cerebro- 
spinal fluid  and  is  contraindicated  in  patients 
suffering  from  head  trauma,  cerebral  hemorrhage, 
etc.  In  some  persons  it  produces  a  reaction  com- 
parable to  shock — nausea,  vomiting,  weakness, 
restlessness,  pallor,  sweating,  syncope  and  incon- 
tinence— due  to  pooling  of  blood  in  the  post- 
arteriolar  vessels  and  failure  of  the  return  of 
venous  blood  to  the  heart  {Arch.  Int.  Med.,  1938, 
62,  97;  /.  Clin.  Inv.,  1938,  17,  41).  Treatment 
consists  of  the  head-low  position,  deep  breathing 
and  exercising  the  extremities  to  aid  venous  re- 
turn; the  reaction  is  aggravated  by  epinephrine.  S 

The  usual  dose  is  0.3  ml.  (approximately  5 
minims),  by  inhalation,  as  required.  The  maxi- 
mum safe  dose  is  0.3  ml.  and  the  total  dose  in  24 
hours  should  rarely  exceed  1.5  ml. 

Storage. — Preserve  "in  tight  containers.  Con- 
tainers for  the  administration  of  Amyl  Nitrite  by 


Part  I 


Anethole 


91 


inhalation  should  be  loosely  wrapped  in  gauze  or 
other  suitable  material."  U.S.P.  Horswell  and 
Silverman  (Ind.  Eng.  Chem.,  Anal.  Ed.,  1941,  13, 
555)  reported  that  amyl  nitrite,  whether  in  vapor 
or  liquid  state,  is  stable  in  air  and  relatively  stable 
when  exposed  to  artificial  light,  but  decomposes 
within  two  hours  when  exposed  to  direct  sunlight. 

AMYLENE  HYDRATE.     U.S.P.,  B.P.,  LP. 

Tertiary  Amyl  Alcohol,  [Amyleni  Hydras] 

C2HB.C(CH3)2.0H 

The  B.P.  defines  amylene  hydrate  as  ethyl- 
dimethylcarbinol  and  states  that  it  may  be  made 
by  hydration  of  amylene  (2-methylbutene-l).  The 
I. P.  defines  the  substance  as  2-methyl-butanol-2. 

Dimethylethylcarbinol;  Tertiary  Pentanol.  Amylenum 
Hydratum;  Hydras  Amylenicus.  Fr.  Hydrate  d'amylene. 
Ger.  Amylenhydrat;  Tertiarer  Amylalkohol.  It.  Idrato  di 
amilene.  Sp.  H idrato  de  Amileno. 

Amylene  hydrate,  an  alcohol,  is  prepared  com- 
mercially by  hydrating  amylene,  a  hydrocarbon 
obtained  by  the  chlorination  of  isopentane  and 
hydrolysis  of  the  resulting  products.  Hydration 
of  the  amylene  is  effected  by  treatment  with  a 
mixture  of  sulfuric  acid  and  water  at  0°;  after 
neutralization  of  the  acid  the  amylene  hydrate  is 
separated  by  distillation. 

Description. — "Amylene  Hydrate  occurs  as 
a  clear,  colorless  liquid,  having  a  camphoraceous 
odor.  Its  solutions  are  neutral  to  litmus.  One  Gm. 
of  Amylene  Hydrate  dissolves  in  about  8  ml.  of 
water.  It  is  miscible  with  alcohol,  with  chloro- 
form, with  ether,  and  with  glycerin.  The  specific 
gravity  of  Amylene  Hydrate  is  not  less  than  0.803 
and  not  more  than  0.807.  Amylene  Hydrate  distils 
completely  between  97°  and  103°."  U.S.P.  The 
I. P.  states  that  at  temperatures  below  —13° 
amylene  hydrate  forms  hygroscopic  acicular 
crystals. 

Standards  and  Tests. — Identification. — (1) 
A  mixture  of  amylene  hydrate,  sulfuric  acid, 
potassium  dichromate  and  water  is  heated  for  2 
hours  under  a  reflux  condenser,  forming  acetic 
acid  and  acetone.  These  are  removed  by  distilla- 
tion. Acetone,  being  the  more  volatile,  distils  over 
first  and  is  identified  in  the  first  portion  of  dis- 
tillate by  test  (2).  The  remainder  of  the  distillate 
is  neutralized  with  sodium  hydroxide  T.S.  and 
evaporated  to  dryness:  the  residue  responds  to 
tests  for  acetate.  (2)  A  deep  red  liquid,  developing 
a  violent  tint  on  dilution  with  water,  is  produced 
when  sodium  nitroprusside  T.S.  is  added  to  a 
dilution  of  the  reserved  distillate,  acidified  slightly 
with  acetic  acid.  (3)  A  violet  red  color  results 
on  adding  5  ml.  of  a  1  in  100  solution  of  vanillin 
in  sulfuric  acid  to  10  ml.  of  a  1  in  10  solution  of 
amylene  hydrate.  Water. — Anhydrous  cupric  sul- 
fate does  not  become  blue  when  agitated  with 
amylene  hydrate.  Non-volatile  residue. — Not  over 
25  mg.  when  10  ml.  of  amylene  hydrate  is  evapo- 
rated and  finally  dried  at  105°  for  1  hour.  Heavy 
metals. — The  limit  is  5  parts  per  million.  Readily 
oxidizable  substances. — The  pink  color  of  a  mix- 
ture of  10  ml.  of  1  in  20  solution  of  amylene 
hydrate  and  0.1  ml.  of  0.1  N  potassium  per- 
manganate is  not  entirely  discharged  in  10  min- 
utes. Aldehyde. — No  darkening  occurs  on  heating 


a  mixture  of  10  ml.  of  1  in  20  solution  of  amylene 
hydrate  and  1  ml.  of  ammoniacal  silver  nitrate 
T.S.  for  10  minutes  at  60°.  U.S.P. 

The  B.P.  test  for  limit  of  water  is  performed 
by  adding  fight  petroleum  to  amylene  hydrate; 
the  resulting  mixture  should  show  no  cloudiness. 

Uses. — In  1887  amylene  hydrate,  a  central 
nervous  system  depressant,  was  proposed  by  Von 
Mering  as  a  hypnotic.  Advantages  claimed  were 
that  it  was  quicker  and  more  potent  than  paral- 
dehyde or  sulfonal,  and  that  it  did  not  depress 
the  heart  like  chloral  hydrate.  As  a  hypnotic  it 
ranks  between  chloral  hydrate  and  paraldehyde 
and  it  is  relatively  non-toxic.  It  was  rarely  used 
until  it  was  employed  as  a  vehicle  for  the  basal 
anesthetic  tribromoethanol.  It  is  official  because 
of  this  use  (see  Tribromoethanol  Solution). 

Harnack  and  Meyer  (Ztschr.  klin.  Med.,  1894, 
24,  374)  reported  it  produced  quiet  sleep  in 
herbivorous  animals  but  was  an  excitant  to  dogs 
and  cats.  It  antagonized  the  convulsant  effects  of 
strychnine,  picrotoxin  and  santonin,  and  in  a 
general  way  its  action  was  like  that  of  alcohol. 
Barlow  and  Gledhill  (/.  Pharmacol,  1933,  49,  36) 
studied  the  effects  of  amylene  hydrate  on  rats 
both  alone  and  combined  with  tribromoethanol. 
They  found  the  lethal  dose,  rectally  or  subcu- 
taneously,  was  about  1.4  Gm.  per  Kg.  Although 
the  rate  of  respiration  was  increased,  the  volume 
of  air  moved  per  minute  was  lessened  by  all  doses. 
While  it  was  possible  to  produce  complete  anes- 
thesia with  amylene  hydrate  it  required  65  per 
cent  of  the  lethal  dose  and  was  accompanied  by 
reduction  of  about  75  per  cent  in  the  volume  of 
air  breathed  (Hofmann,  Arch.  exp.  Path.  Pharm., 
1936,  183,  127). 

In  humans  the  hypnotic  dose,  dissolved  in  glyc- 
erin, is  1  to  4  Gm.  Since  the  average  dose  of 
Tribromoethanol  Solution  contains  over  2  Gm. 
of  amylene  hydrate,  it  may  contribute  to  the 
hypnotic  action  of  this  solution. 

Amylene  hydrate  is  an  important  commercial 
solvent;  it  is  used  especially  in  dry  cleaning  of 
cellulose  acetate  materials. 

Storage. — Preserve  "in  tight  containers." 
U.S.P. 

Off.  Prep. — Tribromoethanol  Solution,  U.S.P. , 
B.P. 

ANETHOLE.     U.S.P. 

Anethol,  [Anethole] 


CH,0 


^  / 


-CH=CHCH3 


"Anethole  is  parapropenyl  anisole.  It  is  ob- 
tained from  anise  oil  and  other  sources,  or  is  pre- 
pared synthetically."  U.S.P. 

Anise  Camphor.  l-Methoxy-4-propenylbenzene. 

Anethole  occurs  in  several  volatile  oils.  From 
80  to  90  per  cent  of  anise  oil  is  anethole;  the 
latter  may  be  separated  by  cooling  the  oil.  Ane- 
thole may  also  be  obtained  from  pine  oil;  indeed 
this  oil  was  the  only  available  source  of  anethole 
when  supplies  of  anise  oil  were  cut  off  during  the 
Second  World  War.  It  may  be  synthesized  from 
anisole  and  acetaldehyde. 


92 


Anethole 


Part   I 


Description. — "Anethole  is  a  colorless  or 
faintly  yellow  liquid  at  or  above  23°.  It  has  a 
sweet  taste,  the  aromatic  odor  of  anise,  and  its 
alcohol  solutions  are  neutral  to  litmus.  It  is  af- 
fected by  light.  Anethole  is  readily  miscible  with 
ether  and  with  chloroform.  It  dissolves  in  2  vol- 
umes of  alcohol.  It  is  slightly  soluble  in  water. 
The  specific  gravity  of  Anethole  is  not  less  than 
0.983  and  not  more  than  0.988."  U.S.P. 

Standards  and  Tests. — Congealing  tempera- 
ture.— Not  less  than  20°.  Distillation  range. — 
Anethole  distils  completely  between  231°  and 
237°.  Optical  rotation. — Anethole  is  optically  in- 
active or  shows  a  rotation  of  not  more  than  0.15° 
in  a  100-mm.  tube.  Refractive  index. — Not  less 
than  1.5570  and  not  more  than  1.5610.  Aldehydes 
and  ketones. — No  appreciable  diminution  in  the 
volume  of  anethole  occurs,  nor  does  a  crystalline 
deposit  form,  when  10  ml.  of  anethole  is  shaken 
with  50  ml.  of  a  saturated  aqueous  solution  of 
sodium  bisulfite  and /allowed  to  stand  6  hours. 
Phenols. — No  purplish  color  is  produced  upon  the 
addition  of  3  drops  of  ferric  chloride  T.S.  to  10 
ml.  of  the  filtrate  separated  from  1  ml.  of  anethole 
shaken  with  20  ml.  of  distilled  water.  U.S. P. 

Anethole  is  used  like,  and  for  the  same  pur- 
poses as,  anise  oil  (which  see). 

Dose,  from  0.06  to  0.3  ml.  (approximately  1  to 
5  minims). 

Storage. — Preserve  "in  tight,  fight-resistant 
containers."  U.S.P. 

Off.  Prep. — Diphenhydramine  Hydrochloride 
Elixir,  U.S.P. ;  Compound  Cardamom  Spirit,  N.F. 

ANISE  OIL.    U.S.P.,  B.P.  (LP.) 

[Oleum  Anisi] 

"Anise  Oil  is  the  volatile  oil  distilled  with  steam 
from  the  dried,  ripe  fruit  of  Pimpinella  Anisum 
Linne  (Fam.  Umbelliferce)  or  from  the  dried,  ripe 
fruit  of  Illicium  verum  Hooker  filius  (Fam.  Mag- 
noliacece).  Note. — If  solid  material  has  separated 
from  Anise  Oil,  carefully  warm  the  mixture 
until  it  is  completely  liquefied,  and  mix  it  thor- 
oughly before  using."  U.S.P.  The  B.P.  and  LP. 
recognize  oil  distilled  from  the  same  plant  sources. 

I. P.  Oil  of  Anise.  Oil  of  Aniseed.  Oleum  Anisi 
^thereum;  Essentia  anisi.  Fr.  Essence  d'anis.  Ger.  Ani- 
sol.  It.  Essenze  di  anice.  Sp.  Esencia  de  anis. 

Anise  oil,  which  is  imported  into  this  country 
chiefly  from  India  and  French  Indo-China,  is  ob- 
tained mostly  from  Illicium  verum,  or  Star  Anise, 
which  is  described  in  Part  II  under  the  title 
Illicium.  For  a  description  of  Pimpinella  Anisum 
see  under  Anise,  in  Part  II. 

Description. — "Anise  oil  is  a  colorless  or  pale 
yellow,  strongly  refractive  liquid,  having  the  char- 
acteristic odor  and  taste  of  anise.  One  volume  of 
Anise  Oil  dissolves  in  3  volumes  of  90  per  cent 
alcohol.  The  specific  gravity  of  Anise  Oil  is  not 
less  than  0.978  and  not  more  than  0.988."  U.S.P. 

Standards  and  Tests. — Congealing  tempera- 
ture.— Not  below  15°.  Optical  rotation. — The 
optical  rotation  in  a  100-mm.  tube,  at  25°,  is  be- 
tween +  1°  and  —2°.  Refractive  index. — Not  less 
than  1.5530  and  not  more  than  1.5600,  at  20°. 
Heavy  metals. — The  oil  meets  the  official  require- 
ments. Phenols. — A  1  in  3  solution  of  recently 


distilled  anise  oil  in  90  per  cent  alcohol  is  neutral 
to  moistened  litmus  paper,  and  the  solution  de- 
velops no  blue  or  brown  color  on  adding  1  drop 
of  ferric  chloride  T.S.  to  5  ml.  of  it.  U.S.P. 

Constituents. — Anise  oil  contains  80  to  90 
per  cent  of  anethole  (which  see),  together  with 
small  amounts  of  its  isomer  methyl-chavicol,  of 
anisaldehyde,  and  of  terpenes. 

Adulterants. — Because  of  its  high  price  anise 
oil  is  often  adulterated.  Spermaceti,  wax  and 
camphor  are  adulterants  that  have  been  used  in 
times  past;  fennel  stearoptene  has  been  found 
also.  The  so-called  Japanese  star  anise  oil  (from 
Illicium  anisatum),  with  which  the  official  oil  may 
be  confused,  is  derived  from  leaves,  rather  than 
fruit,  and  contains  eugenol  and  safrol,  and  much 
less  anethole  than  the  oil  from  the  fruit  (see 
Illicium,  Part  II). 

Uses. — Anise  oil  is  one  of  the  most  popular  of 
flavoring  agents.  Therapeutically  it  is  useful  to 
stimulate  peristalsis  in  colic  and  as  an  expectorant. 
Boyd  and  Pearson  (Am.  J.  Med.  Sc,  1946,  211, 
602)  found  it  to  be  more  effective  than  the  oils  of 
turpentine,  pine,  lemon  or  eucalyptus.  They  be- 
lieve that  the  expectorant  volatile  oils  act  directly 
on  the  secretory  cells  of  the  respiratory  tract. 
Anise  oil  has  also  been  recommended  as  a  means 
of  destroying  body  lice.  Parutz  (Schim.  Rep., 
1920)  used  a  1  per  cent  ointment  for  scabies.  The 
N.F.  IX  recognized  Anise  Spirit,  a  10  per  cent 
v/v  solution  of  the  oil  in  alcohol,  also  Anise 
Water,  a  saturated  solution  of  the  oil  in  distilled 
water. 

Dose,  of  the  oil,  0.2  to  0.3  ml.  (approximately 
3  to  5  minims). 

Storage. — Preserve  "in  well-filled,  tight  con- 
tainers and  avoid  exposure  to  excessive  .heat." 
U.S.P. 

Off.  Prep. — Glycyrrhiza  Syrup;  Compound 
Orange  Spirit,  U.S. P.;  Aromatic  Cascara  Sagrada 
Fluidextract;  Camphorated  Opium  Tincture, 
U.S. P.,  B.P.;  Compound  Sarsparilla  Syrup,  N.F. 

ANTAZOLINE  HYDROCHLORIDE. 

U.S.P..  LP. 

Antazolinium  Chloride,  2-(N-Benzylanilinomethyl)-2- 
imidazoline  Hydrochloride 


\        \-CH2-N-CH2-r^   ^ 

^ '  ^-^  HM 1 


HN- 


cr 


"Antazoline  Hydrochloride,  dried  at  105°  for  3 
hours,  contains  not  less  than  98  per  cent  of 
C17N19N3.HCI."  U.S.P.  The  LP.  rubric  is  the 
same,  referred  to  the  substance  as  it  occurs. 

I. P.  Antazolini  Hydrochloridum.  2-(N-Phenyl-N-benzyl- 
aminomethyl)imidazoline  Hydrochloride.  Antistine  Hydro- 
chloride  (Ciba).  Phenazoline  Hydrochloride. 

This  antihistaminic  substance  is  characterized 
by  the  fact  that  the  side  chain  (see  article  on 
Antihistaminic  Drugs,  in  Part  II),  which  in  many 
such  compounds  is  a  dialkylaminoethyl  group,  has 
been   replaced  by   an  imidazoline   radical,   thus 


Part  I 


Antazoline   Hydrochloride  93 


making  antazoline  similar  to  the  sympathomimetic 
drugs  Privine  [2-(l-naphthylmethyl)-2-imidazo- 
line]  and  Otrivine  [(2-anilinomethyl)-2-imidazo- 
line] .  Antazoline  may  be  synthesized  by  the  inter- 
action of  anilinomethylimidazoline  and  benzyl 
chloride,  the  first  reactant  being  prepared  from 
anilinoacetimidoester  and  ethylenediamine  (see 
Idson,  Chem.  Rev.,  1950,  47,  340). 

Description. — "Antazoline  Hydrochloride  oc- 
curs as  a  white,  odorless,  crystalline  powder.  Its 
solutions  are  neutral  to  litmus.  One  Gm.  of 
Antazoline  Hydrochloride  dissolves  in  about  40 
ml.  of  water,  and  in  about  25  ml.  of  alcohol.  It 
is  practically  insoluble  in  chloroform,  in  ether, 
and  in  benzene.  Antazoline  Hydrochloride  melts, 
with  decomposition,  between  232°  and  238°." 
U.S.P. 

Standards  and  Tests. — Identification. — (1) 
A  deep  red  color  is  produced  when  25  mg.  of 
antazoline  hydrochloride  is  dissolved  in  5  ml.  of 
nitric  acid,  the  color  persisting  when  the  solution 
is  diluted  with  20  ml.  of  water.  (2)  A  1  in  100,000 
solution  exhibits  an  ultraviolet  absorbancy  maxi- 
mum at  242  mn  ±  1  mjx,  and  a  minimum  at  222 
m\t  ±  1  mn;  the  specific  absorbancy,  E(l%, 
1  cm.),  at  242  m\i  is  between  495  and  515.  (3) 
Antazoline  hydrochloride  responds  to  tests  for 
chloride.  Loss  on  drying. — Not  over  0.5  per  cent, 
when  dried  at  105°  for  3  hours.  Residue  on  igni- 
tion.— Not  over  0.2  per  cent.  U.S.P. 

Assay. — About  600  mg.  of  antazoline  hydro- 
chloride, dried  at  105°  for  3  hours,  is  dissolved  in 
80  ml.  of  glacial  acetic  acid  and,  after  adding 
10  ml.  of  mercuric  acetate  T.S.,  is  titrated  with 
0.1  N  perchloric  acid,  the  end-point  being  deter- 
mined potentiometrically.  Each  ml.  of  0.1  N 
perchloric  acid  represents  30.18  mg.  of  C17H19- 
N3.HCI.  U.S.P.  This  non-aqueous  titration  is 
based  upon  the  principle  that  each  molecule  of 
antazoline  base  represented  in  the  sample  releases 
one  acetate  ion  when  the  salt  is  dissolved  in  acetic 
acid.  Each  acetate  ion,  being  basic,  in  turn  com- 
bines with  a  hydrogen  ion  released  by  perchloric 
acid,  forming  a  molecule  of  acetic  acid.  Since  the 
solvent  medium  is  acetic  acid,  this  reaction  is  one 
of  neutralization,  comparable  to  the  combination 
of  hydrogen  and  hydroxyl  ions  to  form  water 
when  the  latter  is  the  solvent  medium.  The  pur- 
pose of  adding  mercuric  acetate  is  to  prevent  in- 
terference by  the  hydrochloride  component  of  the 
salt,  which  reacts  with  the  mercuric  acetate  to 
form  acetic  acid  and  non-ionized  mercuric  chlo- 
ride (for  additional  information  see  Kleckner  and 
Osol,  /.  A.  Ph.  A.,  1952,  41,  573).  The  LP.  assays 
the  substance  gravimetrically  as  the  picrate. 

Uses. — This  drug  has  received  extensive  phar- 
macological and  clinical  study.  Its  antihistaminic 
activity  in  animals  is  10  to  20  per  cent  of  that  of 
tripelennamine  hydrochloride,  but  its  toxicity  is 
likewise  low  (Meier  and  Bucher,  Schweiz.  med. 
Wchnschr.,  1946,  76,  294;  Craver  et  al.,  Ann. 
Allergy,  1951,  9,  34).  Used  prophylactically,  it 
protects  the  guinea  pig  from  anaphylactic  shock 
and  in  human  skin  it  prevents  wheal  formation 
following  injection  of  histamine  or  of  the  specific 
allergen  in  the  allergic  patient  (Serafini,  /.  Allergy, 
1948,  19,  256;  Schwartz  and  Wolf,  ibid.,  1949, 
20,  32).  Dutta  (Brit.  J.  Pharmacol.  Chemother., 


1949,  4,  281)  reported  it  to  have  2.3  times  the 
local  anesthetic  effect  of  procaine  hydrochloride; 
he  also  observed  it  to  have  antiacetylcholine  action 
and  a  more  intense  effect  than  that  of  quinidine 
in  decreasing  the  response  of  muscle  to  electrical 
stimulation.  Its  use  does  not  prevent  a  positive 
tuberculin  patch  test  (Kendig  et  al.,  J.  Pediat., 
1949,  35,  750)  and  it  does  not  increase  or  de- 
crease the  antibody  titer  following  diphtheria- 
tetanus  toxoid  (Regamey  and  Wantz,  Schweiz.  Zt. 
Path.  Bakt.,  1947,  10,  426). 

Many  clinical  reports  have  appeared  on  its  use 
in  allergic  disorders.  A  number  of  these  have  been 
summarized  by  Loveless  and  Dworin  (Bull.  N.  Y. 
Acad.  Med.,  1949,  25,  473),  with  the  general  con- 
clusion that  while  a  lower  percentage  of  thera- 
peutic effectiveness  was  found  than  with  most 
other  antihistamines,  the  incidence  of  untoward 
effects  was  likewise  among  the  lowest.  Friedlaender 
and  Friedlaender  (Ann.  Allergy,  1948,  6,  23)  con- 
cluded that  100  mg.  of  antazoline  hydrochloride 
is  clinically  equivalent  to  50  mg.  of  tripelennamine 
hydrochloride.  Antazoline  was  found  to  be  the 
least  effective  of  13  antihistaminics  tested  by 
Sternberg  et  al.  (J.A.M.A.,  1950,  142,  969)  for 
ability  to  raise  the  histamine  whealing  threshold 
in  man. 

Antazoline  absorbs  the  erythema-producing 
wave  lengths  of  the  ultraviolet  region  (Fried- 
laender et  al,  J.  Invest.  Derm.,  1948,  11,  397). 
Studies  of  the  living  mesoappendix  by  Haley  and 
Harris  (/.  Pharmacol,  1949,  95,  293)  showed 
that  it  causes  contraction  of  the  precapillary 
sphincter. 

Since  it  is  less  irritating  than  some  other  anti- 
histaminics antazoline  hydrochloride  is  used  in  an 
0.5  per  cent  buffered  (pH  6.1)  isotonic  solution 
in  the  conjunctival  sac  (see  reference  to  use  of 
antazoline  phosphate  below)  and  the  nose  (Fried- 
laender and  Friedlaender,  loc.  cit.).  Hurwitz  (Am. 
J.  Ophth.,  1948,  31,  1409)  reported  relief  of 
allergic  eye  conditions  with  one  drop  of  this  solu- 
tion applied  every  3  or  4  hours;  momentary 
smarting  was  observed.  Taub  et  al.  (Am.  Pract., 
1949,  3,  664),  however,  do  not  advise  use  of  this 
solution  because  of  the  short  period  of  sympto- 
matic relief  and  the  danger  of  sensitizing  the 
tissue  to  the  drug.  A  solution  containing  0.025  per 
cent  naphazoline  hydrochloride  and  0.5  per  cent 
antazoline  hydrochloride  is  intended  for  nasal  use 
by  application  in  the  form  of  drops,  spray,  or  by 
tampon;  the  antihistamine  component  also  pos- 
sesses vasoconstrictive  action.  The  solution  is  in- 
dicated in  allergic  and  vasomotor  rhinitis,  sinusitis 
and,  perhaps,  in  the  common  cold.  A  concentra- 
tion in  excess  of  1:1000  inhibits  ciliary  activity 
(Craver  et  al,  loc.  cit.).  See  also  the  general  dis- 
cussion of  Antihistaminic  Drugs  in  Part  II. 

The  untoward  effects  are  similar  to  those  of 
other  antihistamines  but  the  incidence  is  lower, 
with  the  possible  exception  of  thonzylamine. 
Nausea  and  drowsiness  are  most  frequent.  Intra- 
venously the  drug  must  be  given  very  slowly  to 
minimize  flushing  and  vertigo;  the  dose  by  this 
route  should  not  exceed  50  to  100  mg. 

Dose. — The  usual  dose  is  100  mg.  (approxi- 
mately \Yz  grains)  up  to  4  times  daily  by  mouth, 
with  a  range  of  50  to  100  mg.  The  maximum  safe 


94  Antazoline   Hydrochloride 


Part  I 


dose  is  100  mg.  and  the  total  dose  in  24  hours 
should  generally  not  exceed  400  mg. 

A  0.5  per  cent  solution  in  isotonic  sodium 
chloride  solution  is  used  in  the  nose.  For  oph- 
thalmic use,  a  0.5  per  cent  isotonic  solution  of 
Antazoline  Phosphate  (N.N.R.),  is  preferable  to 
that  prepared  from  the  hydrochloride  because  it 
produces  less  smarting  and  stinging. 

Storage. — Preserve  "in  tight,  light-resistant 
containers."  U.S.P. 

ANTAZOLINE  HYDROCHLORIDE 
TABLETS.     U.S.P. 

"Antazoline  Hydrochloride  Tablets  contain  not 
less  than  93  per  cent  and  not  more  than  107  per 
cent  of  the  labeled  amount  of  C17H19N3.HCI." 
U.S.P. 

Assay. — The  antazoline  hydrochloride  in  a 
representative  portion  of  powdered  tablets  is  ex- 
tracted with  alcohol  and  the  content  of  the  active 
ingredient  calculated  from  observation  of  the 
absorbancy  at  the  wavelength  of  maximum  ab- 
sorption, in  this  case  242  mn.  While  the  position 
of  the  absorbancy  maximum  in  the  case  of  anta- 
zoline hydrochloride  is  the  same  in  both  alcohol 
and  water  solution,  which  is  not  the  case  with  all 
antihistaminic  drugs  similarly  assayed,  there  is 
somewhat  more  intense  absorption  in  alcohol  solu- 
tion, which  accounts  for  the  difference  in  values 
of  specific  absorbancy  given  for  the  water  solution 
employed  in  identification  test  (2)  under  anta- 
zoline hydrochloride  and  for  the  alcohol  solution 
employed  in  the  assay  of  the  tablets.  U.S.P. 

Usual  Size. — 100  mg.  (approximately  1J^ 
grains). 

ANTHRALIN.     N.F.  (B.P.) 

[Anthralinum] 
0  H         OH         OH 


"Anthralin.  dried  over  sulfuric  acid  for  4  hours, 
contains  not  less  than  95  per  cent  of  C14H10O3." 
N.F.  Under  the  title  Dithranol  the  B.P.  defines 
this  substance  as  1,8-dihydroxyanthranol;  no  assay 
rubric  is  stipulated. 

B.P.  Dithranol.  Dioxyanthranol;  1,8,9-Anthratriol. 
Cignolin  (Winthrop). 

This  chrysarobin  substitute  may  be  synthesized 
by  reducing  l,S-dihydroxyanthraquinone,  the  lat- 
ter obtained  by  heating  with  lime  the  1,8-anthra- 
quinonedisulfonic  acid  prepared  by  sulfonation  of 
anthraquinone  in  the  presence  of  mercury. 

The  1,8-dihydroxyanthraquinone,  which  is  the 
parent  substance  of  anthralin,  is  closely  related 
to  chrysophanol,  structurally  l,8-dihydroxy-3- 
methylanthraquinone,  which  is  the  parent  com- 
pound of  the  constituents  of  chrysarobin  (q.v.) 
and  is  itself  an  important  constituent  of  cascara, 
rhubarb  and  senna.  As  might  be  expected,  1.8-di- 
hydroxyanthraquinone  is  laxative,  being  official 
as  Danthron. 


Description. — "Anthralin  occurs  as  an  odor- 
less, tasteless,  crystalline,  yellowish  brown  pow- 
der. When  suspended  in  water  and  filtered,  the 
filtrate  is  neutral  to  litmus  paper.  Anthralin  is 
soluble  in  chloroform,  in  acetone,  and  in  benzene. 
It  is  soluble  in  solutions  of  alkali  hydroxides.  It 
is  slightly  soluble  in  alcohol,  in  ether,  and  in 
glacial  acetic  acid.  It  is  insoluble  in  water.  An- 
thralin melts  between  175°  and  181V'  N.F.  The 
B.P.  indicates  anthralin  to  be  soluble  in  fixed  oils. 
Standards  and  Tests. — Identification. — (1) 
A  yellowish  to  orange  solution,  having  a  green 
fluorescence,  results  when  anthralin  is  dissolved 
in  sodium  hydroxide  T.S.;  on  exposure  to  air  the 
solution  turns  to  a  strong  orange-red  color.  (2) 
A  greenish  brown  color  is  produced  when  anthra- 
lin is  dissolved  in  alcohol  and  ferric  chloride  T.S. 
is  added.  Chloride. — Addition  of  silver  nitrate 
T.S.  to  a  saturated  solution  of  anthralin  produces 
no  opalescence.  Sulfate. — Addition  of  barium 
chloride  T.S.  to  a  saturated  solution  of  anthralin 
produces  no  turbidity.  Loss  on  drying. — Not  over 
0.5  per  cent,  when  dried  over  sulfuric  acid  for  4 
hours.  Residue  on  ignition. — The  residue  from  500 
mg.  is  negligible.  N.F.  The  B.P.  specifies,  as  a  test 
to  exclude  dihydroxyanthracene,  that  100  mg.  of 
anthralin  should  dissolve  completely  in  5  ml.  of 
hot  benzene,  forming  a  clear  yellow  or  orange 
solution.  As  a  test  to  exclude  dihydroxy anthra- 
quinone 1  mg.  is  required  to  produce  a  clear 
orange  solution  in  a  few  drops  of  sulfuric  acid,  no 
trace  of  violet  color  being  evident.  The  loss  on 
drying  to  constant  weight  at  100°  should  not  be 
more  than  1  per  cent  and  the  ash  should  not  ex- 
ceed 0.1  per  cent. 

Assay. — Using  a  chloroform  solution  contain- 
ing 0.01  mg.  of  anthralin  per  ml.  optical  .density 
readings  are  taken  at  354  mn  and  at  432  mn  in  a 
suitable  spectrophotometer  and  the  corresponding 
values  of  E(l%,  1  cm.)  are  calculated.  The  con- 
tent of  anthralin  is  calculated  by  means  of  an 
equation  utilizing  a  difference  function  of  the  E 
values.  iVJ7.  No  assay  is  specified  by  the  B.P. 

Uses. — Anthralin  has  the  action  and  uses  of 
chrysarobin  (q.v.)  over  which  it  has  several  ad- 
vantages, as  follows:  It  is  a  definite  compound, 
rather  than  an  indefinite  mixture;  it  is  effective 
at  lower  concentrations;  it  is  less  irritant  to  the 
skin,  conjunctiva  and  kidneys;  it  causes  less 
coloration  of  clothing  (Beerman  et  al.,  J. A.M. A., 
1935,  104,  26,  48). 

Anthralin  is  used  in  psoriasis,  dermatophytoses, 
chronic  eczemas,  alopecia  areata  and  other  dis- 
eases of  the  skin  in  which  a  stimulant  application 
is  indicated.  Goodman  (Arch.  Derm.  Syph.,  1939, 
40,  76)  warned  against  its  prolonged  use  because 
exhaustion  of  the  epidermal  tissues  may  result. 
The  drug  should  be  discontinued  if  pustular 
folliculitis  or  renal  irritation  develops. 

Anthralin  is  usually  employed  in  concentrations 
of  0.1  to  1  per  cent,  in  the  form  of  an  ointment 
or  cream,  in  a  benzene  solution,  or  in  a  collodion 
vehicle;  the  lowest  concentration  should  be  em- 
ployed first,  then  increased  if  found  necessary 
and  well-tolerated. 

Storage. — Preserve  "in  tight  containers,  pro- 
tected from  light."  N.F. 


Part  I 


Antimony  Potassium  Tartrate  95 


ANTHRALIN  OINTMENT.     N.F.  (B.P.) 

[Unguentum  Anthralinum] 

"Anthralin  Ointment  labeled  to  contain  more 
than  0.1  per  cent  of  anthralin  (C14H10O3)  con- 
tains not  less  than  90  per  cent  and  not  more  than 
115  per  cent  of  the  labeled  quantity  of  C14H10O3 
and  contains  not  more  than  115  per  cent  of 
C14H10O3  and  1,8-dihydroxyanthraquinone  (C14- 
H8O4)  combined.  Not  more  than  10  per  cent  of 
the  labeled  quantity  of  anthralin  is  C14H8O4. 

"Anthralin  Ointment  labeled  to  contain  0.1  per 
cent  or  less  of  C14H10O3  contains  not  less  than 
90  per  cent  and  not  more  than  130  per  cent  of 
the  labeled  quantity  of  C14H10O3  and  not  more 
than  130  per  cent  of  C14H10O3  and  C14H8O4  com- 
bined. Not  more  than  20  per  cent  of  the  labeled 
quantity  of  anthralin  is  C14H8O4."  N.F. 

B.P.  Ointment  of  Dithranol;  Unguentum  Dithranolis. 

Anthralin  ointment  may  be  prepared  by  thor- 
oughly mixing  10  Gm.  of  finely  powdered  anthra- 
lin with  a  portion  of  white  petrolatum  and  then 
incorporating  sufficient  white  petrolatum  to  make 
1000  Gm.  Due  to  slow  oxidation  of  anthralin  to 
1,8-dihydroxyanthraquinone  upon  standing,  oint- 
ments intended  not  to  be  used  for  some  time 
should  be  prepared  with  about  5  per  cent  excess 
of  anthralin  for  ointments  containing  more  than 
0.1  per  cent,  and  a  20  per  cent  excess  of  anthralin 
for  ointments  containing  0.1  per  cent  or  less.  N.F. 

The  B.P.  recognizes  Ointment  of  Dithranol, 
containing  0.1  per  cent  of  dithranol  in  a  base  of 
yellow  soft  paraffin  (yellow  petrolatum),  and  a 
Strong  Ointment  of  Dithranol,  containing  1  per 
cent  of  dithranol  in  the  same  base. 

For  uses  of  anthralin  ointment,  see  the  preced- 
ing monograph. 

Storage. — Preserve  "in  well-closed,  light- 
resistant  containers."  N.F. 


ANTIMONY 
Sb  (121.76) 

Stibium.  Fr.  Antimoine.  Ger.  Antimon.  It.  Antimonio. 
Sp.  Antimonio. 

Antimony,  earlier  called  stibium,  may  have  been 
known  as  long  ago  as  4000  B.C.  In  ancient  times 
it  was  employed  as  a  medicine  and  as  a  cosmetic. 
Late  in  the  15th  century  Basil  Valentine  described 
its  preparation  and  his  observations  of  properties 
of  the  element  and  some  of  its  compounds. 

The  free  element  is  found  in  nature  in  rela- 
tively small  amounts.  Its  chief  ore,  stibnite 
(Sb2S3),  occurs  rather  abundantly,  especially  in 
China,  Mexico,  Bolivia,  Algeria,  Portugal  and 
France;  comparatively  few  deposits  have  been 
found  in  the  United  States.  The  metal  is  obtained 
either  by  heating  stibnite  with  scrap  iron,  or  by 
roasting  the  ore  to  convert  it  to  oxides  of  anti- 
mony which  are  subsequently  reduced  to  metal 
by  heating  with  carbon. 

Properties. — Antimony  is  a  brittle,  brilliant 
metal,  ordinarily  of  a  lamellated  texture,  of  a 
silver-white  color  when  pure,  but  bluish  white  as 
it  occurs  in  commerce.  Its  density  is  about  6.7, 
and  it  melts  at  630°.  When  heated  in  oxygen  it 


burns  with  a  bright  bluish  flame,  forming  the 
trioxide.  Several  allotropic  forms  may  be  pre- 
pared by  special  treatment.  It  forms  three  com- 
binations with  oxygen,  antimony  trioxide  (anti- 
monious  oxide),  SD2O3,  antimony  tetr oxide,  Sb204 
(by  some  considered  to  be  an  antimonate  of  the 
radical  antimonyl,  SbO.SbOs),  and  antimony  pent- 
oxide  (antimonic  oxide),  Sb20s. 

By  virtue  of  the  fact  that  antimony  has  the 
property  of  imparting  hardness  to  metals,  par- 
ticularly lead,  it  is  used  in  the  manufacture  of 
lead  alloy  for  storage  battery  plates,  in  Babbitt 
metal  and  other  antifriction  alloys,  in  pewter  and 
Britannia  metal,  in  type  metal,  and  in  other  alloys. 
It  has  the  important  property  of  expanding  on 
cooling  which,  in  type  metal,  makes  it  possible 
to  obtain  an  accurate  cast  of  a  letter.  Antimony 
has  been  used  as  an  alloy  with  lead  for  shrapnel 
and  the  bullet  cores  of  small  arms  ammunition. 
One  of  the  important  newer  uses  of  compounds 
of  antimony  is  that  of  antimony  trioxide  in  flame- 
proofing  compounds  for  application  to  military 
and  household  textiles.  Large  amounts  of  anti- 
mony trisulfide  and  antimony  pentasulfide  are 
used  in  the  rubber  industry  for  producing  vul- 
canized rubber  of  red  color. 

Inorganic  antimony  compounds  are  not  em- 
ployed in  therapeutics  because  of  their  toxicity, 
but  a  number  of  organic  compounds  are  safe 
enough  to  use.  The  activity  of  antimonials  is 
proportional  not  merely  to  their  solubility  in  the 
gastric  juices  but,  according  to  the  researches  of 
Brunner  (Arch.  exp.  Path.  Pharm.,  1912,  68, 
186),  especially  depends  upon  whether  the  metal 
is  in  the  trivalent  or  pentavalent  condition,  the 
latter  being  comparatively  innocuous  (see  the 
study  by  Goodwin,  /.  Pharmacol.,  1944,  81,  224). 
In  recent  years  organic  preparations  of  antimony 
have  received  considerable  attention  as  thera- 
peutic agents  in  various  protozoal  diseases  (see 
Antimony  Potassium  Tartrate,  Antimony  Sodium 
Thiogly collate,  Stibophen,  and  the  article  on  Anti- 
monials, Organic,  in  Part  II).  For  a  comprehen- 
sive report  on  the  toxicology  of  antimony  see 
Fairhall  and  Hyslop  (Supplement  No.  195  to  the 
Public  Health  Reports,  1947). 

ANTIMONY  POTASSIUM  TARTRATE 
U.S.P.,  B.P.  (LP.) 

Antimonyl  Pot.'.ssium  Tartrate,  Tartar  Emetic, 
[Antimonii  Potassi  Tartras] 

"Antimony  Potassium  Tartrate  contains  not  less 
than  99  per  cent  of  C4H4K07Sb.^H20."  U.S.P. 
The  B.P.  and  LP.  rubrics  are  the  same. 

I. P.  Potassium  Antimonyltartrate ;  Stibii  et  Kalii 
Tartras.  Tartrated  Antimony.  Antimonium  Tartaratum; 
Tartarus  Stibiatus;  Kalium  Stibio  Tartaricum;  Stibii  et 
Potassii  Tartras;  Tartarus  Emeticus.  Fr.  Antimoniotar- 
trate  acide  de  potassium;  Tartre  stibie;  Tartrate  d'anti- 
moine  et  de  potasse.  Ger.  Brechweinstein ;  Weinsaures 
Antimonylkalium.  It.  Tartrato  di  antimonio  e  di  potas- 
sio;  Tartaro  stibiato.  Sp.  Tartrato  de  antimonio  y  de 
potasio;    Tartrato  Potdsico  Antimonico;   Tartaro   estibiado. 

Antimony  potassium  tartrate  may  be  prepared 
by  the  interaction  of  antimony  trioxide  and  potas- 
sium bitartrate. 

The  structure  of  this  salt  is  a  subject  of  contro- 
versy. Reihlen  and  Hezel  (Ann.  Chem.,  1931,  487, 


96  Antimony   Potassium   Tartrate 


Part  I 


213)  proposed  a  cyclic  structure  in  which  the 
water  is  attached  by  coordination  to  the  antimony, 
as  follows: 


0:C 


OH2 


Evidence  for  this  cyclic  structure  has  been  ob- 
tained also  by  Pfeiffer  and  Schmitz  (Pharmazie, 
1949,  4,  451). 

Description. — "Antimony  Potassium  Tartrate 
occurs  as  colorless,  odorless,  transparent  crystals, 
or  as  a  white  powder.  The  crystals  effloresce  upon 
exposure  to  air.  Its  solutions  are  acid  to  litmus. 
One  Gm.  of  Antimony  Potassium  Tartrate  dis- 
solves in  12  ml.  of  water  and  in  about  15  ml.  of 
glycerin.  One  Gm.  dissolves  in  about  3  ml.  of  boil- 
ing water.  It  is  insoluble  in  alcohol.  U.S.P. 

Standards  and  Tests. — Identification. — (1) 
Antimony  potassium  tartrate  chars,  emits  an  odor 
like  that  of  burning  sugar,  and  leaves  a  blackened 
residue  when  heated  to  redness;  the  residue  is 
alkaline  and  confers  a  violet  tint  to  a  non-lumi- 
nous flame.  (2)  An  orange  red  precipitate  forms 
on  adding  hydrogen  sulfide  T.S.  to  a  1  in  10  solu- 
tion of  antimony  potassium  tartrate,  acidified  with 
hydrochloric  acid;  the  precipitate  dissolves  in  am- 
monium sulfide  T.S.  and  in  sodium  hydroxide  T.S. 
Arsenic. — The  limit  is  200  parts  per  million. 
U.S.P.  The  B.P.  limits  for  arsenic  and  lead  are 
8  parts  per  million  and  5  parts  per  million,  re- 
spectively; the  corresponding  LP.  limits  are  10 
parts  per  million  and  5  parts  per  million. 

Assay. — About  500  mg.  of  antimony  potassium 
tartrate  is  dissolved  in  water,  a  saturated  solution 
of  sodium  bicarbonate  is  added,  and  the  trivalent 
antimony  is  oxidized  to  the  pentavalent  state  by 
titration  with  0.1  N  iodine,  employing  starch  T.S. 
indicator.  Each  ml.  of  0.1  N  iodine  represents 
16.70  mg.  of  C4H4K07Sb.^H20.  U.S.P.  The 
B.P.  and  LP.  assays  are  practically  identical  with 
that  of  the  U.S.P. 

Incompatibilities. — Mineral  acids  added  to 
aqueous  solutions  of  tartar  emetic  precipitate  the 
respective  basic  salts  of  antimony,  with  possibly 
some  potassium  bitartrate.  Alkali  hydroxides  and 
carbonates,  in  sufficient  amounts,  precipitate  anti- 
mony trioxide,  soluble  in  excess  of  fixed  alkali. 
The  precipitation  may  be  prevented  by  an  excess 
of  citrates,  tartrates,  glycerin,  or  sugar.  Most 
metallic  salts,  including  those  of  lead  and  silver, 
form  insoluble  tartrates  when  added  to  aqueous 
solutions  of  tartar  emetic.  Tannic  and  gallic  acids, 
or  infusions  of  tannin-containing  drugs,  yield 
precipitates  with  tartar  emetic.  Solutions  of  al- 
bumin and  of  soap  behave  similarly.  Lime  water 
forms  insoluble  calcium  and  antimony  tartrates; 
mercuric  chloride  is  reduced  to  calomel. 

Uses. — Tartar  emetic  is  a  slow-acting  local 
irritant,  capable  of  causing  not  only  redness  but 
also  vesicles  and  pustules  at  the  orifices  of  the 
glands  of  the  skin;  this  action  appears  to  be 
associated  with  the  formation  of  antimony  tri- 
oxide. It  has  been  used  as  a  counterirritant  in 
the  form  of  an  ointment  or  plaster. 


When  taken  internally,  tartar  emetic  provokes 
salivation  and  nausea;  in  sufficient  dose  active 
vomiting  occurs.  The  emetic  effect  is  the  result 
chiefly  of  the  local  irritant  action  of  antimony 
upon  the  gastric  mucosa.  This  is  true  even  when 
the  drug  is  injected  hypodermicWly,  because  it  is 
excreted  through  the  walls  of  the  stomach  in 
sufficient  quantity  to  act  as  an  irritant.  On  the 
other  hand,  the  drug  will  produce  vomiting  move- 
ments in  the  dog  even  after  complete  removal  of 
the  stomach  (Hatcher  and  Weiss,  /.  Exp.  Med., 
1923,  37,  97).  Tartar  emetic  is  poorly  absorbed 
from  the  gastrointestinal  tract. 

When  absorbed  into  the  circulation,  as  by  in- 
travenous injection,  the  antimony  solution  causes 
a  marked  lowering  of  blood  pressure,  decreased 
cardiac  output,  dilatation  of  the  splanchnic  ves- 
sels, increased  pressure  in  the  pulmonary  vessels 
and,  in  large  doses,  respiratory  depression.  Changes 
in  the  electrocardiogram  occur  in  patients  treated 
with  antimony  compounds,  more  frequently  when 
tartar  emetic  is  used  than  when  other  organic 
antimonials  are  employed;  these  changes  have 
not  been  permanent  and  seemed  to  have  no  seri- 
ous clinical  import  (see  Mainzer  and  Krause, 
Trans.  Roy.  Soc.  Trop.  Med.  Hyg.,  1940,  33, 
405;  Tarr,  Bull.  U.  S.  Army  M.  Dept.,  1946,  5, 
336;  Schroeder  et  ah,  Am.  J.  Med.  Sc,  1946, 
212,  697). 

Tartar  emetic  is  excreted  rapidly  (see  also 
under  Stibophen) ,  elimination  being  almost  com- 
plete in  72  hours.  It  is  found  in  the  urine;  large 
doses  cause  signs  of  renal  irritation.  Kramer 
{Bull.  Johns  Hopkins  Hosp.,  1950,  86,  179)  re- 
ported a  higher  concentration  of  antimony  in  the 
thyroid  of  the  rabbit  than  in  any  other  tissue 
except  the  fiver  but  no  histological  or  functional 
abnormality  was  observed. 

While  it  is  a  powerful  emetic,  antimony  has 
been  almost  completely  abandoned  for  such  use 
in  favor  of  less  dangerous  and  equally  efficient 
emetic  drugs.  It  is,  however,  still  occasionally  em- 
ployed as  a  nauseant  expectorant  in  the  treatment 
of  acute  bronchitis  and  is  an  ingredient  of  some 
cough  syrups.  Its  use  should  be  avoided  in  very 
young  or  very-  old  persons,  also  in  persons  with 
feeble  circulation. 

Tartar  emetic  and  other  antimony  compounds 
(see  Stibophen  and  Antimonials,  Organic)  have 
been  used  widely  in  treating  various  tropical  in- 
fections. Chemotherapy  with  heavy  metal  com- 
pounds usually  depends  on  a  differential  toxicity 
whereby  the  parasites  are  destroyed  or  made  sus- 
ceptible to  cellular  or  humoral  defense  mechan- 
isms of  the  body  by  a  dose  of  the  metallic  com- 
pound which  is  insufficient  to  cause  serious  damage 
to  the  host;  while  this  general  statement  is 
applicable  to  antimony  compounds,  the  exact 
mechanism  of  their  action  has  not  been  elucidated 
(see  Most  and  Lavietes,  Medicine,  1947,  26,  221). 
In  an  in  vitro  study  of  several  antimony  com- 
pounds Mansour  {Brit.  J.  Pharmacol.  Chemother., 
1951,  6,  588)  observed  paralysis  of  the  liver  fluke. 
Fasciola  hepatica,  only  if  50  per  cent  of  blood 
serum  was  added  to  a  1:1000  solution  of  tartar 
emetic;  stibophen  was  not  active,  either  alone  or 
in  the  presence  of  serum. 


Part  I 


Antimony   Potassium   Tartrate  97 


In  schistosomiasis  japonica,  the  War  Depart- 
ment, U.S.A.  (TB  Med  167,  see  War  Med.,  1945, 
7,  397)  recommended  use  of  Fuadin  (see  Stibo- 
phen)  or  antimony  potassium  tartrate.  The  latter 
is  administered  intravenously,  slowly,  about  2  or 
3  hours  after  a  light  meal.  The  needle  must  be 
wiped  off  before  insertion  and  there  must  be  no 
extravasation  of  the  solution.  The  patient  should 
remain  recumbent  for  at  least  an  hour  after  the 
injection.  For  the  first  dose  8  ml.  of  0.5  per  cent 
solution  is  given;  on  alternate  days  the  dose  is 
increased  by  4  ml.  each  time  until  a  maximum 
dose  of  28  ml.  is  reached,  which  is  repeated  15 
times.  Coughing  immediately  upon  injection  is  a 
common  though  unimportant  untoward  effect; 
this  may  be  minimized  by  injecting  slowly,  at  a 
rate  not  exceeding  8  ml.  per  minute.  Other  toxic 
manifestations  include  nausea,  vomiting,  stiffness 
of  the  joints  and  muscles,  sensation  of  constric- 
tion in  the  chest,  pain  in  the  epigastrium,  brady- 
cardia, dizziness  and  collapse;  if  any  of  these 
symptoms  occurs  during  the  injection,  it  should 
be  stopped.  Subsequent  doses  should  be  decreased 
or  omitted  entirely,  depending  on  the  severity  of 
the  reaction.  If  viable  eggs  persist  four  weeks 
after  the  completion  of  the  course  of  injections, 
the  course  should  be  repeated,  or  another  drug 
employed,  if  the  patient  can  tolerate  it.  When 
instituted  early,  this  treatment  prevents  develop- 
ment of  severe  sequelae.  If  cirrhosis  of  the  liver 
has  developed,  the  treatment  cannot  correct  it. 
Injections  should  not  be  given  in  the  presence  of 
severe  disease  of  the  heart,  liver  or  kidney.  Gen- 
erally, other  heavy  metals  or  emetine  should  not 
be  given  at  the  same  time.  Beneficial  effects  have 
been  obtained  with  similar  treatment  regimens 
employed  against  Schistosoma  mansoni  and 
S.  haematobium  (see  the  extensive  review  Ad- 
vances in  the  Therapeutics  of  Antimony,  Schmidt 
and  Peter,  Leipzig,  1938).  Successful  treatment 
of  a  case  of  cerebral  schistosomiasis  manifesting 
Jacksonian  convulsive  seizures  has  also  been  re- 
ported (Salis  and  Smith,  Ann.  Int.  Med.,  1951, 
34,  238). 

For  granuloma  inguinale  (characterized  by  the 
presence  of  Donovan  bodies  in  the  lesion  and  not 
to  be  confused  with  the  venereal,  "virus"  disease 
lymphogranuloma  inguinale),  the  "broad-spec- 
trum" antibiotics,  such  as  aureomycin  (q.v.),  have 
proved  to  be  more  effective,  safer  and  much  easier 
to  use  than  antimony  compounds.  Tartar  emetic 
has,  however,  been  rather  extensively  employed, 
one  of  the  treatment  programs,  recommended 
when  a  course  of  stibophen  had  failed  after  six 
weeks  (see  TB  Med  157,  Bull.  U.  S.  Army  M. 
Dept.,  1945,  4,  326),  consisting  of  the  initial  in- 
jection of  3  ml.  of  1  per  cent  solution,  given 
slowly  intravenously,  repeated  on  alternate  days 
with  an  increase  in  the  dose  of  3  ml.  each  time 
until  12  ml.  is  reached,  which  is  given  15  times. 

Tartar  emetic  was  the  first  successful  form  of 
therapy  for  visceral  leishmaniasis  (kala-azar), 
but  the  treatment  was  prolonged,  uncomfortable 
and  difficult,  with  toxic  effects  often  preventing 
satisfactory  clinical  results;  it  is  therefore  not 
recommended  for  such  use,  Neostibosan  (see 
Part  II)   being  advised  instead.   Tartar  emetic 


has  been  used  effectively  in  the  treatment  of 
oriental  sore.  Mucocutaneous  leishmaniasis  in 
South  America  has  been  treated  with  an  initial 
dose  of  4  ml.  of  a  1  per  cent  solution  of  tartar 
emetic,  this  being  increased  by  1  ml.  at  each  in- 
jection to  a  maximum  dose  of  10  ml.,  at  which 
level  injections  were  given  twice  weekly  for  about 
six  weeks  (Snow  et  al.,  Arch.  Dermat.  Syph., 
1948,  57,  90) ;  combined  therapy  with  arsenic 
and  antimony  (stibophen)  is,  however,  preferred. 

Tartar  emetic  has  been  employed  in  trypano- 
somiasis but  arsenicals  (see  Tryparsamide)  are 
less  toxic,  and  diamidines  (see  in  Part  II)  seem 
to  be  more  effective.  It  has  failed  in  the  treatment 
of  clonorchiasis ;  it  is  of  possible  value  in  filariasis 
but  is  not  recommended  (War  Med.,  1945,  7, 
377).  Cochrane  (Med.  Press,  May  9,  1945)  ad- 
vised on  alternate  days  3  doses  of  20  mg.  fol- 
lowed by  3  doses  of  40  mg.  for  the  true  lepra- 
reaction  in  leprosy.  It  has  been  employed  for 
trachoma  with  corneal  complications  (Brit.  M.  J., 
1939,  1,  516)  and  for  trypanosomiasis  in  cattle 
(Cawston,  /.  Trop.  Med.  Hyg.,  1935,  38,  305). 
It  was  also  recommended  by  Rogers  (Brit.  M.  J., 
Jan.  6,  1917)  for  the  destruction  of  the  crescents 
in  the  treatment  of  tertian  malarial  fever.  Grove 
(J.A.M.A.,  1925,  85,  349)  reported  a  case  of 
trichinosis  in  which  the  larvae  were  demonstrated 
in  the  blood  stream,  and  in  which,  following  the 
intravenous  injection  of  a  solution  of  tartar 
emetic,  the  symptoms  promptly  subsided  and  the 
parasites  disappeared  from  the  blood.  Tomlinson 
and  Bancroft  (J.A.M.A.,  1934,  102,  36)  reported 
two  cases  of  that  rare  and  often  fatal  mycodermal 
infection  known  as  granuloma  coccidioides,  which 
were  apparently  cured  by  its  intravenous  use. 

Tartar  emetic  has  recently  been  recommended 
as  a  spray  in  the  control  of  thrips  on  lemons, 
gladioli,  and  onions.  lYl 

Poisoning. — Symptoms  of  acute  poisoning  by 
the  drug  are  an  austere  metallic  taste,  excessive 
nausea,  copious  vomiting,  frequent  hiccough, 
burning  pain  in  the  stomach,  colic,  frequent  stools 
and  tenesmus,  fainting,  rapid  and  feeble  pulse, 
coldness  of  the  skin,  and  even  of  the  internal 
organs,  difficult  and  irregular  respiration,  cutane- 
ous anesthesia,  convulsive  movements,  painful 
cramps  in  the  legs,  anuria,  prostration,  and  death. 
In  rare  cases  vomiting  and  purging  do  not  take 
place,  and  when  they  are  absent,  the  other  symp- 
toms are  aggravated.  Sometimes  a  pustular  erup- 
tion is  produced,  like  that  caused  by  the  external 
application  of  the  antimonial.  Although  because 
of  the  promptness  of  its  emetic  action  recovery 
may  occur  after  very  large  amounts,  one  case  is 
on  record  in  which  130  mg.  proved  fatal. 

The  symptoms  of  antimony  poisoning  fre- 
quently so  closely  resemble  those  of  arsenic  that 
a  diagnosis  may  be  well-nigh  impossible  except 
through  chemical  examinations.  The  post-mortem 
lesions  also  resemble  those  of  arsenic  poisoning; 
commonly  ulcerations  are  found  in  the  esophagus 
and  stomach — although  sometimes  lacking — but 
rarely  in  the  intestines.  In  the  less  acute  cases 
there  also  develop  fatty  degenerations  of  the 
liver,  kidneys  or  heart,  and  sometimes  also  de- 
generative changes  in  the  nervous  system. 


98  Antimony   Potassium   Tartrate 


Part   I 


In  the  treatment  of  antimony  poisoning,  even 
though  the  patient  has  vomited,  it  is  usually 
advisable  to  wash  out  the  stomach,  using  a  solu- 
tion of  tannic  acid.  Tannic  acid  should  be  ad- 
ministered repeatedly  as  the  poison  is  eliminated 
from  the  blood  through  the  walls  of  the  stomach. 
The  use  of  milk  or  albumin  water  as  demulcents, 
opiates  to  check  the  diarrhea  and  relieve  the  pain, 
and  various  stimulants  should  be  employed  as 
symptoms  may  indicate.  Rosenthal  and  Severn 
(Arch.  exp.  Path.  Pharm.,  1912,  67,  275)  asserted 
that  potassium  hexatantalate  is  capable  of  fol- 
lowing the  drug  after  its  absorption  and  producing 
a  non-toxic  compound  in  the  system.  Dimercaprol 
(g.v.)  decreased  the  mortality  of  animals  poisoned 
with  tartar  emetic  and  several  organic  antimonial 
compounds  (Eagle  et  al.,  J.  Pharmacol.,  1947,  89, 
196;  Braun  et  al,  ibid.,  Suppl.,  1946,  87,  119). 
In  all  cases  of  suspected  poisoning,  the  vomit,  the 
passages  from  the  bowels,  and  especially  the  urine 
should  be  reserved  for  chemical  examination.  The 
metal  has  been  found  in  all  the  tissues  of  the  body 
and  is  most  abundant  in  the  liver. 

Dose. — The  dose  of  tartar  emetic  varies 
greatly  according  to  the  purpose  for  which  it  is 
employed.  As  a  diaphoretic  or  expectorant  it  may 
be  given  2  or  3  times  daily  in  doses  of  2  to  8  mg. 
(approximately  %o  to  y&  grain)  by  mouth.  If 
used  as  an  oral  emetic,  the  dose  is  usually  about 
30  to  60  mg.  (approximately  Y  to  1  grain). 

As  an  intravenous  injection  in  the  treatment 
of  protozoal  or  other  infections  it  is  usually  given 
in  the  form  of  a  0.5  to  1  per  cent  solution  in  dis- 
tilled water,  normal  saline  or  dextrose-saline  solu- 
tion. The  drug  is  preferably  taken  from  a  freshly 
opened  container  and  dissolved  in  a  sterile  solvent 
with  aseptic  precautions  although  sterilization  may 
be  accomplished  by  boiling  gently  for  5  minutes 
or  by  filtration;  solutions  should  not  be  auto- 
claved  (War  Med.,  1945,  7,  403,  but  see  steriliza- 
tion method  described  under  Injection  of  Anti- 
mony Potassium  Tartrate).  For  doses  employed 
see  under  Uses.  The  U.S. P.  gives  the  usual  in- 
travenous dose  as  40  mg.  (approximately  Yz 
grain),  in  the  form  of  0.5  per  cent  solution,  three 
times  a  week,  with  a  range  of  dose  of  20  to  100 
mg.;  the  maximum  single  dose  is  100  mg.,  which 
should  not  be  exceeded  in  24  hours,  and  the  total 
course  should  not  exceed  1.5  to  2  Gm. 

Great  care  is  required  in  injecting  these  solu- 
tions because  of  the  danger  of  very  troublesome 
cellulitis  if  any  should  escape  into  the  surrounding 
tissues. 

Storage. — Preserve  "in  well-closed  contain- 
ers." U.S.P. 

Off.  Prep. — Compound  Opium  and  Glycyr- 
rhiza  Mixture;  Compound  Squill  Syrup,  NJ?. 

INJECTION  OF  ANTIMONY 
POTASSIUM  TARTRATE.     B.P.  (LP.) 

Injection  of  Potassium  Antimonyltartrate,  Injectio 
Antimonii  et  Potassii  Tartratis 

This  injection  is  a  sterile  solution  of  antimony 
potassium  tartrate  in  water  for  injection,  the  solu- 
tion being  sterilized  by  heating  in  an  autoclave 
(115°  to  116°  for  30  minutes)  or  by  filtration 
-through  a  bacteria-proof  filter.  It  is  required  to 


contain  not  less  than  94.0  per  cent  and  not  more 
than  105.0  per  cent  of  the  labeled  amount  of  anti- 
mony potassium  tartrate.  B.P.  The  LP.  limits  for 
Injection  of  Potassium  Antimonyltartrate  are  the 
same.  For  uses  and  dose  see  the  preceding  mono- 
graph. 

ANTIMONY  SODIUM  TARTRATE. 
B.P.  (LP.) 

Sodium  Antimonyltartrate,  Antimonii  et  Sodii  Tartras 

Antimony  Sodium  Tartrate  is  made  by  the  in- 
teraction of  antimonious  oxide  and  sodium  acid 
tartrate.  It  contains  not  less  than  96.0  per  cent 
of  C4H407SbNa,  with  reference  to  the  substance 
dried  to  constant  weight  at  105°;  the  LP.  specifies 
the  same  rubric  but  refers  to  the  substance  dried 
at  110°. 

I. P.  Sodium  Antimonyltartrate;  Stibii  et  Natrii 
Tartras. 

Description  and  Standards. — Antimony  so- 
dium tartrate  occurs  as  colorless  and  transparent, 
or  whitish,  scales  or  powder,  it  is  odorless,  has  a 
sweetish  taste,  and  is  hygroscopic.  It  dissolves  in 
1.5  parts  of  water  but  is  insoluble  in  alcohol.  It 
responds  to  tests  for  sodium,  antimony,  and  tar- 
trates. Not  more  than  2  ml.  of  either  0.01  N 
sulfuric  acid  or  0.01  AT  sodium  hydroxide  is  re- 
quired to  bring  the  pH  of  a  solution  containing 
1  Gm.  in  50  ml.  to  a  pH  of  4.5  (corresponding  to 
a  green  color  with  bromocresol  green).  The 
arsenic  limit  is  8  parts  per  million;  the  lead  limit 
is  5  parts  per  million.  At  105°  it  loses  not  more 
than  6.0  per  cent  of  its  weight. 

Assay. — The  assay  is  as  described  under  Anti- 
mony Potassium  Tartrate.  Each  ml.  of  0.1  N 
iodine  represents  15.44  mg.  of  C4H40-SbNa.  B.P. 
The  LP.  assay  differs  from  that  of  the  B.P.  only 
in  minor  details. 

Uses. — Antimony  sodium  tartrate  is  used  for 
the  same  therapeutic  purposes  and  in  about  the 
same  dose  as  tartar  emetic  (see  Antimony  Potas- 
sium Tartrate).  It  has  the  advantages  over  the 
potassium  salt  of  being  considerably  more  soluble 
in  aqueous  media,  and  less  irritant  when  injected. 

Doses. — As  an  expectorant,  2  to  8  mg.  (ap- 
proximately %o  to  y&  grain) ;  as  an  emetic,  30  to 
60  mg.  (approximately  Y  to  1  grain) ;  as  a  proto- 
zoicide,  30  to  120  mg.  (approximately  Y  to  2 
grains),  by  intravenous  injection.  |v] 

Storage. — Sodium  Antimony  Tartrate  should 
be  kept  in  a  well-closed  container.  LP. 

INJECTION  OF  ANTIMONY  SODIUM 
TARTRATE.     B.P.  (LP.) 

Injection  of  Sodium  Antimonyltartrate,  Injectio 
Antimonii  et  Sodii  Tartratis 

This  injection  is  a  sterile  solution  of  antimony 
sodium  tartrate  in  water  for  injection,  the  solu- 
tion being  sterilized  by  heating  in  an  autoclave 
(115°  to  116°  for  30  minutes)  or  by  filtration 
through  a  bacteria-proof  filter.  It  is  required  to 
contain  not  less  than  85.5  per  cent  and  not  more 
than  105.0  per  cent  of  the  labeled  content  of  anti- 
mony sodium  tartrate.  B.P.  The  corresponding 
LP.  limits  for  Injection  of  Sodium  Antimonyl- 
tartrate are  95.0  and  105.0  per  cent,  respectively. 
For  uses  and  dose  see  the  preceding  monograph. 


Part  I 


Antipyrine  99 


SODIUM  ANTIMONYLTHIOGLY- 
COLLATE.    I.P. 

Stibii  et  Natrii  Thio'glycollas 

/S.CH2.COONa 

Sbr 


\s.cH2.coo 


"Antimony  Sodium  Thioglycollate,  dried  at 
105°  for  2  hours,  contains  not  less  than  96  per 
cent  and  not  more  than  101  per  cent  of  C-tHtNaO-i- 
S2SD."  U.S.P.  XIV.  The  I.P.  requires  not  less  than 
35.5  per  cent  and  not  more  than  38.5  per  cent  of 
Sb,  calculated  with  reference  to  the  substance 
dried  at  100°  for  4  hours. 

U.S.P.  XIV.  Antimony  Sodium  Thioglycollate.  Sp. 
Tioglicolato  de  Sodio  y  Antimonio. 

Antimony  sodium  thioglycollate  may  be  ob- 
tained by  dissolving  antimony  trioxide  in  a  solu- 
tion containing  an  equimolecular  mixture  of  thio- 
glycollic  acid  and  sodium  thioglycollate;  on  evapo- 
rating the  solution  the  salt  is  obtained. 

Description. — "Antimony  Sodium  Thioglycol- 
late occurs  as  a  white  or  pink  powder.  It  is  odorless 
or  has  a  faint  mercaptan  odor,  and  is  discolored 
by  light.  Antimony  Sodium  Thioglycollate  is 
freely  soluble  in  water.  It  is  insoluble  in  alcohol." 
U.S.P.  XIV. 

Standards  and  Tests. — Identification. — (1) 
A  transient  blue  color  is  produced  on  adding  1 
drop  of  diluted  hydrochloric  acid  and  2  drops  of 
a  1  in  100  ferric  chloride  solution  to  3  ml.  of  a  1 
in  100  solution  of  antimony  sodium  thioglycol- 
late; on  subsequently  adding  1  drop  of  dilute  am- 
monia T.S.  (1  in  10)  a  deep  red  color  is  produced. 
(2)  A  white  precipitate  is  produced  on  adding  1 
ml.  of  sodium  hydroxide  T.S.  to  3  ml.  of  a  1  in  100 
solution  of  antimony  sodium  thioglycollate.  (3) 
An  orange  precipitate  is  produced  on  passing  hy- 
drogen sulfide  into  a  solution  of  100  mg.  of  anti- 
mony sodium  thioglycollate  in  2  ml.  of  water. 
Loss  on  drying. — Not  over  2  per  cent  when  dried 
at  105°  for  2  hours.  U.S.P.  XIV. 

Assay. — About  600  mg.  of  antimony  sodium 
thioglycollate,  previously  dried  at  105°  for  2 
hours,  is  dissolved  in  water  containing  hydro- 
chloric acid.  After  adding  tartaric  acid  hydrogen 
sulfide  is  passed  into  the  solution  until  precipita- 
tion of  antimonous  sulfide  is  complete;  the  pre- 
cipitate is  successively  washed  with  hydrogen  sul- 
fide T.S.,  alcohol,  ether,  carbon  disulfide,  alcohol 
and  ether,  and  dried  to  constant  weight.  The 
weight  of  sulfide  multiplied  by  1.913  represents 
the  equivalent  in  terms  of  C4H4Na04S2Sb.  U.S.P. 
XIV.  The  I.P.  assay  is  practically  identical. 

Uses. — This  trivalent  antimonial  was  reported 
by  Randall  (Am.  J.  Med.  Sc,  1924,  168,  723)  to 
be  less  toxic  and  more  effective  than  antimony 
potassium  tartrate  in  the  treatment  of  granuloma 
inguinale  (due  to  Leishmania  donovani).  He  ad- 
vised at  least  12  doses  to  be  administered  after 
the  healing  of  the  lesion.  These  findings  were  con- 
firmed by  Patch  and  Blew  (Can.  Med.  Assoc.  J., 
1930,  23,  637)  and  by  Senear  and  Cornbleet 
(Arch.  Dermat.  Syph.,  1932,  25,  167).  The  com- 
pound has  also  been  employed  in  treating  kala- 
azar.  It  has  proved  to  be  less  toxic  than  antimony 
thioglycollamide  (see  in  Part  II),  but  also  less 


stable;  as  is  generally  true  of  the  trivalent  anti- 
monials,  it  is  more  toxic  than  the  pentavalent 
derivatives. 

Dose. — From  50  to  100  mg.  (approximately 
Yi,  to  1^2  grains),  dissolved  in  10  to  20  ml.  of 
sterile  distilled  water,  may  be  given  every  third 
or  fourth  day,  intravenously,  subcutaneously  or 
intramuscularly,  for  15  or  25  doses. 

Storage. — Preserve  "in  tight,  light-resistant 
containers."  U.S.P.  XIV. 

INJECTION  OF  SODIUM  ANTI- 
MONYLTHIOGLYCOLLATE.    I.P. 

Injectio  Stibii  et  Natrii  Thioglycollatis 

This  injection  is  a  sterile  solution  of  sodium 
antimonylthioglycollate  in  water  for  injection; 
1.0  per  cent  of  sodium  citrate  and  0.1  per  cent  of 
thioglycollic  acid  may  be  used  for  preservation; 
the  solution  is  sterilized  by  heating  in  an  autoclave 
(30  minutes  at  115°  to  116°)  or  by  filtration 
through  a  bacteria-proof  filter.  The  content  of 
sodium  antimonylthioglycollate  (C4H404S2SbNa) 
is  not  less  than  93.0  per  cent  and  not  more  than 
107.0  per  cent  of  the  labeled  amount. 

Storage. — Preserve  preferably  in  single-dose, 
hermetically-closed  containers,  or  in  multiple- 
dose  containers,  protected  from  light.  I.P. 

ANTIPYRINE.     N.F.   (I.P.) 

Phenazone,  [Antipyrina] 


CH, 


./ 


CH, 


V3 


H 


The  I.P.  defines  Phenazone  as  2  : 3 -dimethyl- 1- 
phenyl-5-pyrazolone. 

I.P.  Phenazone ;  Phenazonum.  Phenyldimethylpyra- 
zolonum;  Pyrazolonum  Phenyldimethylicum.  Fr.  Phenyl- 
dim^thylpyrazolone;  Dimethyloxyquinizine.  Ger.  Phenyl- 
dimethylpyrazolon;  Antipyrin.  It.  Fenil-dimetilisopira- 
zolone;  Antipirina.  Sp.  Antipirina;  Fenazona. 

Antipyrine  was  one  of  the  first  important  syn- 
thetic medicinals ;  it  was  introduced  into  medicine 
in  1887  as  a  result  of  research  by  Knorr  directed 
toward  the  preparation  of  compounds  possessing 
a  quinine-like  structure.  Structually  it  is  1,5-di- 
methyl-2-phenyl-3-pyrazolone,  named  according  to 
the  standard  nomenclature  used  in  the  United 
States,  or  l-phenyl-2,3-dimethyl-5-pyrazolone,  if 
the  tautomeric  designation  followed  by  the  I.P. 
is  used.  Antipyrine  may  be  classed  as  a  derivative 
of  pyrrole,  C4H5N,  found  in  coal  tar,  or  more 
directly  of  pyrazole,  which  differs  from  pyrrole  in 
having  an  atom  of  nitrogen  in  the  number  two 
position  in  place  of  —  CH=  in  pyrrole.  Pyrazole 
has  the  formula 

H 


HC5 


2N 


HC- 


-CH 


and  is  isomeric  with  imidazole  (the  parent  com- 
pound of  histamine) ;   in  imidazole  the  tertiary 


100  Antipyrine 


Part   I 


nitrogen  is  at  the  number  three  position  (see  under 
Histamine  Phosphate). 

Synthesis  of  antipyrine  may  be  effected  in  sev- 
eral ways.  In  one  process  phenylhydrazine, 
Cr,H.-.XH.XH2,  is  heated  with  ethyl  acetoacetate, 
(CH3CO)CH2.COOC2H5)  to  form  the  phenylhy- 
drazone  of  ethyl  acetoacetate  which  loses  a  mole- 
cule of  alcohol  and  forms  a  phenyl-methyl-pyra- 
zolone;  this  is  methylated  to  antipyrine.  Other 
syntheses  use  methylphenylhydrazine  along  with 
the  enol  form  of  ethyl  acetoacetate  or  a  halogen- 
crotonic  ethyl  ester  without  subsequent  methyla- 
tion. 

Description. — "Antipyrine  occurs  as  colorless 
crystals,  or  as  a  white,  crystalline  powder.  It  is 
odorless,  has  a  slightly  bitter  taste,  and  its  solu- 
tions are  neutral  to  litmus  paper.  One  Gm.  of 
Antipyrine  dissolves  in  less  than  1  ml.  of  water, 
in  1.3  ml.  of  alcohol,  in  1  ml.  of  chloroform,  and 
in  43  ml.  of  ether.  Antipyrine  melts  between  110° 
and  112.5°."  N.F.    , 

Standards  and  Tests. — Identification. — (1) 
A  white  precipitate  forms  on  adding  tannic  acid 
T.S.  to  an  aqueous  solution  of  antipyrine.  (2)  A 
nearly  colorless  solution  results  on  adding  100 
mg.  of  sodium  nitrite  to  12  ml.  of  a  1  in  100  solu- 
tion of  antipyrine ;  addition  of  1  ml.  of  diluted  sul- 
furic acid  produces  a  deep  green  color.  (3)  A 
deep  red  color  forms  when  one  drop  of  ferric 
chloride  T.S.  is  added  to  2  ml.  of  a  1  in  1000 
solution  of  antipyrine;  on  adding  10  drops  of  sul- 
furic acid  the  color  changes  to  a  light  yellow.  (4) 
An  orange-yellow  precipitate  forms  on  heating  to 
boiling  a  mixture  of  100  mg.  antipyrine,  100  mg. 
vanillin,  5  ml.  of  distilled  water,  and  2  ml.  of  sul- 
furic acid.  Loss  on  drying. — Not  over  1  per  cent, 
when  dried  at  60°  for  2  hours.  Residue  on  ignition. 
— Xot  over  0.15  per  cent.  Heavy  metals. — The 
limit  is  20  parts  per  million.  Completeness  and 
color  of  solution. — Antipyrine  dissolves  com- 
pletely in  an  equal  weight  of  cold  distilled  water, 
forming  a  colorless  or  not  more  than  slightly  yel- 
low (viewed  transversely  in  a  tube  of  20  mm. 
diameter)  solution.  N.F. 

Incompatibilities. — Antipyrine  is  precipi- 
tated by  most  of  the  alkaloidal  reagents,  including 
potassium  mercuric  iodide,  iodine,  mercuric  chlo- 
ride, and  tannic  acid.  It  partially  decomposes 
calomel  with  the  production  of  mercuric  chloride 
and  metallic  mercury,  the  mixture  darkening  in 
color.  This  reaction  is  more  rapid  in  the  presence 
of  sodium  bicarbonate.  With  nitric  acid  it  be- 
comes first  yellow  and  later  red.  With  nitrites 
such  as  ethyl  nitrite,  the  green  compound  iso- 
nitrosoantipyrine  is  formed.  With  ferric  salts  a 
red  color  is  produced.  With  copper  salts  a  green 
color  is  produced.  It  liquefies  or  forms  a  soft  mass 
when  triturated  with  acetanilid,  betanaphthol, 
chloral,  phenol,  phenyl  salicylate,  pyrogallol,  so- 
dium salicylate,  and  thymol. 

Uses. — Locally  antipyrine  exercises  an  anes- 
thetic effect  upon  the  nerve  endings  (see  Sollman, 
J. A.M. A.,  1918,  70,  216)  and  causes  constriction 
of  the  superficial  vessels.  When  ingested  it  acts 
as  an  analgesic  and  mild  antipyretic.  It  has  been 
used  in  measurement  of  body  water  in  humans 
(see  Soberman,  /.  Biol.  Chem.,  1949,  179,  31). 


Brodie  and  Axelrod  (/.  Pharmacol,  1950,  98, 
97)  found  antipyrine  to  be  completely  absorbed 
from  the  gastrointestinal  tract  and  then  to  be 
evenly  distributed  throughout  the  body  water. 
Only  about  5  per  cent  of  the  drug  is  excreted  in 
the  urine,  the  remainder  being  metabolized  in 
the  body. 

Antipyrine  is  useful  in  medicine  for  the  relief 
of  pain,  as  neuralgias,  myalgias,  migraine  and 
similar  conditions.  Its  action  is  more  prompt  than 
that  of  aniline  derivatives  but  it  has  lost  favor 
to  the  less  toxic  and  equally  effective  salicylates. 
It  is  less  effective  that  aminopyrine  but  it  is  not 
known  to  have  caused  agranulocytosis.  It  has  been 
used  in  certain  spasmodic  disorders,  especially 
whooping-cough  and  epilepsy.  Antipyrine  has  also 
been  used  as  a  mild  antipyretic. 

In  the  treatment  of  various  inflammatory  con- 
ditions of  the  mucous  membranes,  as  rhinitis  and 
laryngitis,  antipyrine  is  sometimes  employed  for 
its  local  anesthetic  and  vasoconstricting  effects. 
For  this  purpose  it  is  usually  applied  in  strengths 
of  from  5  to  15  per  cent.  It  is  occasionally  used 
as  a  styptic  in  nasal  hemorrhage,  [v] 

Toxicology. — Antipyrine  occasionally  pro- 
duces unpleasant  and  sometimes  alarming  symp- 
toms, even  after  doses  which  would  scarcely  be 
regarded  as  excessive.  The  most  common  type  of 
antipyrine  poisoning  is  characterized  by  giddiness, 
tremor,  free  sweating  with  more  or  less  collapse, 
a  peculiar  lividity  with,  in  many  cases,  eruption 
of  the  skin  most  commonly  morbilliform,  but 
sometimes  erythematous  or  urticarial.  It  causes 
less  cyanosis  than  does  acetanilid.  After  very 
large  doses  there  may  be  drowsiness,  deepening 
into  coma,  with  dilatation  of  the  pupil  and  epilep- 
tiform convulsions.  Various  irregular  symptoms 
have  been  noted,  such  as  amaurosis,  pseudomem- 
branous stomatitis,  swelling  of  the  lips  and  tongue, 
laryngeal  interference  with  the  respiration.  In 
some  cases  fever  with  nervous  unrest  and  epilepti- 
form convulsions  have  been  reported. 

The  treatment  of  antipyrine  poisoning  is  purely 
symptomatic.  Circulatory  stimulants,  as  ammonia, 
strychnine  and  atropine,  should  be  given  and  the 
bodily  temperature  maintained  by  external  appli- 
cation of  heat. 

Dose. — The  usual  dose  is  300  mg.  (approxi- 
mately 5  grains);  the  I.P.  gives  the  usual  daily 
dose  as  1  Gm.  but  indicates  that  as  much  as  1  Gm. 
at  a  time,  and  4  Gm.  daily,  may  be  given. 

Storage. — Preserve  "in  tight  containers."  N.F. 

N.F.  ANTISEPTIC  SOLUTION.     N.F. 

Liquor  Antisepticus  N.F. 

Dissolve  25  Gm.  of  boric  acid  in  650  ml.  of  hot 
purified  water  and  allow  the  solution  to  cool.  Dis- 
solve 0.5  Gm.  of  thymol,  0.5  Gm.  of  chlorothymol, 
0.5  Gm.  of  menthol,  0.1  ml.  of  eucalyptol,  0.2  ml. 
of  methyl  salicylate,  and  0.01  ml.  of  thyme  oil  in 
300  ml.  of  alcohol.  Mix  the  two  solutions  and 
add  sufficient  purified  water  to  make  1000  ml. 
Keep  the  product  in  a  tightly  closed  container 
during  2  hours  or  more,  cool  to  10°  and  filter  at 
this  temperature,  using  purified  talc,  if  necessary, 
to  clarify  the  product.  Note. — Specially  denatured 


Part  I 


Apomorphine   Hydrochloride  101 


alcohol  Formula  No.  38-B,  prepared  by  adding 
6  pounds  of  boric  acid  and  V/z  pounds  each  of 
thymol,  chlorothymol,  and  menthol  to  100  gallons 
of  ethyl  alcohol,  has  been  approved  by  the  U.  S. 
Treasury  Department  as  being  suitable  for  use  in 
making  this  solution  provided  that  adjustment  is 
made  for  the  quantities  of  formula  ingredients  in 
the  denatured  alcohol.  N.F. 

Description. — "N.F.  Antiseptic  Solution  is  a 
clear,  colorless  liquid  having  an  aromatic  odor  and 
a  characteristic  taste.  It  is  acid  to  litmus  paper. 
The  specific  gravity  of  N.F.  Antiseptic  Solution 
is  about  0.971."  N.F. 

Tests. — Quantitative  test  for  boric  acid. — The 
intensity  of  color  produced  on  adding  a  turmeric 
solution  to  N.F.  antiseptic  solution  is  not  less  than 
that  developed  by  adding  the  turmeric  solution 
to  a  2.3  w/v  per  cent  solution  of  boric  acid  in  a 
30  in  100  solution  of  alcohol  in  water.  Antibac- 
terial test. — To  5  ml.  of  N.F.  antiseptic  solution 
is  added  0.5  ml.  of  a  standard  culture  of  Staphylo- 
coccus aureus,  both  having  been  kept  at  37.5° 
before  mixing;  after  mixing,  the  liquid  is  also 
kept  at  this  temperature.  After  exactly  5  minutes, 
a  standard  loopful  of  the  mixture  is  transferred 
to  each  of  3  subculture  tubes  containing  10  ml. 
of  standard  culture  medium  and  the  tubes  incu- 
bated at  37.5°  for  48  hours,  at  the  end  of  which 
time  no  bacterial  growth  appears  in  the  tubes. 
For  information  concerning  the  standard  culture, 
the  standard  culture  medium,  and  the  standard 
loopful  reference  should  be  made  to  the  National 
Formulary. 

Alcohol  Content. — From  26  to  29  per  cent, 
by  volume,  of  C2H5OH.  N.F. 

Uses. — Although  this  preparation  is  an  anti- 
septic it  is  too  much  to  expect  that  its  use  in  the 
mouth — which  is  the  reason  for  its  existence — will 
have  material  influence  on  the  oral  flora.  As  ordi- 
narily used  by  the  laity,  adequate  time  is  not 
provided  for  the  solution  to  exert  its  full  effect; 
moreover,  constant  flow  of  saliva  dilutes  and 
washes  away  this  and  any  other  soluble  antiseptic. 
But  the  solution  is  useful  as  a  deodorant  wash 
and  is  probably  as  valuable  for  this  purpose  as 
any  proprietary  solution  on  the  market.  The  N.F. 
recommends  that  the  wash  be  used  undiluted. 

Storage. — Preserve  "in  tight  containers." 
N.F. 

APOMORPHINE  HYDROCHLORIDE. 
U.S.P.,  B.P.,  LP. 

Apomorphinium  Chloride,   [Apomorphinae 
Hydrochloridum] 


CH3.H 


cr.^Hp 


"Apomorphine  Hydrochloride  is  the  hydrochlo- 
ride of  an  alkaloid  prepared  from  morphine." 


U.S.P.  XIV.  The  B.P.  requires  it  to  contain  not 
less  than  83.0  per  cent  of  C17H17NO2,  calculated 
with  reference  to  the  substance  dried  to  constant 
weight  at  105°.  The  LP.,  like  the  U.S.P.,  has  no 
assay  requirement. 

I. P.  Apomorphini  Hydrochloridum.  Apomorphinum 
Hydrochloricum;  Chloretum  Apomorphinicum;  Apomorphi- 
num Chlorhydricum.  Fr.  Chlorhydrate  d'apomorphine. 
Ger.  Apomorphinhydrochlorid;  Salzsaures  Apomorphin.  It. 
Cloridrato  di   apomorfina.  Sp.  Clorhidrato  de  apomorfina. 

Apomorphine,  in  the  form  of  its  sulfate,  was 
first  prepared  by  Arppe  in  1845.  The  base  is 
obtained  by  the  elimination  of  the  elements  of  a 
molecule  of  water  from  a  molecule  of  morphine 
on  heating  the  latter  alkaloid  in  the  presence  of 
acids;  a  slight  rearrangement  of  the  molecular 
structure  occurs  simultaneously.  In  one  process, 
apomorphine  is  prepared  by  heating  morphine 
with  eight  times  its  weight  of  concentrated  hydro- 
chloric acid  in  a  suitable  glass-lined  autoclave 
for  2  or  3  hours  at  140°  to  150°.  After  evaporat- 
ing a  portion  of  the  free  acid,  the  apomorphine 
hydrochloride  crystallizes  on  cooling.  The  crude 
product  is  purified  by  recrystallization.  Because 
of  the  ease  of  oxidation,  exposure  to  air  must  be 
avoided  as  much  as  possible.  Apomorphine  may 
also  be  made  from  codeine,  which  is  a  methyl- 
morphine. 

Apomorphine  base  crystallizes  with  one  mole- 
cule of  water.  It  is  soluble  in  alcohol,  acetone, 
chloroform ;  sparingly  soluble  in  ether  or  benzene, 
and  insoluble  in  petroleum  benzin.  According  to 
Heiduschka  and  Meisner  {Arch.  Pharm.,  1923) 
apomorphine  sublimes  in  a  vacuum.  Apomorphine, 
in  the  form  of  its  dimethyl  ether,  has  been  syn- 
thesized by  Pschorr  and  Avenarius,  and  by  Spaeth 
and  Hromatka  {Ber.,  1929). 

Description. — "Apomorphine  Hydrochloride 
occurs  as  minute,  white  or  grayish  white,  glisten- 
ing crystals  or  white  powder.  It  is  odorless.  It 
gradually  acquires  a  green  color  on  exposure  to 
light  and  air.  Its  solutions  are  neutral  to  litmus. 
One  Gm.  of  Apomorphine  Hydrochloride  dissolves 
in  about  50  ml.  of  water  and  in  about  50  ml.  of 
alcohol.  One  Gm.  dissolves  in  about  20  ml.  of 
water  at  80°.  It  is  very  slightly  soluble  in  chloro- 
form and  in  ether."  U.S.P. 

Standards  and  Tests. — Identification. — (1) 
A  white  or  greenish  white  precipitate  is  formed  on 
adding  a  slight  excess  of  a  1  in  20  solution  of 
sodium  bicarbonate  to  5  ml.  of  a  1  in  100  solution 
of  apomorphine  hydrochloride.  On  adding  to  this 
3  drops  of  iodine  T.S.  and  shaking,  an  emerald 
green  solution  is  produced.  If  this  mixture  is 
shaken  with  5  ml.  of  ether  and  the  layers  are 
allowed  to  separate,  a  deep  ruby  red  color  is  ob- 
served in  the  ether  layer  while  the  aqueous  phase 
remains  green.  (2)  A  dark  purple  solution  is 
formed  when  apomorphine  hydrochloride  is  dis- 
solved in  nitric  acid.  (3)  A  white  precipitate,  in- 
soluble in  nitric  acid,  results  when  silver  nitrate 
T.S.  is  added  to  a  solution  of  apomorphine  hydro- 
chloride; the  precipitate  soon  turns  black  because 
of  reduction  to  metallic  silver.  Addition  of  am- 
monia T.S.  hastens  the  reduction.  Water. — Not 
over  3.5  per  cent,  determined  by  drying  500  mg. 
of  apomorphine  hydrochloride  at  105°  for  2  hours. 


102  Apomorphine    Hydrochloride 


Part   I 


Specific  rotation. — Not  less  than  —49°  and  not 
more  than  —51°,  determined  in  0.02  N  hydro- 
chloric acid  containing  the  equivalent  of  150  mg. 
of  anhydrous  apomorphine  hydrochloride  in  each 
10  ml.  Color  of  solution. — A  solution  of  100  mg.  of 
apomorphine  hydrochloride  in  10  ml.  of  oxygen- 
free  distilled  water  has  no  more  color  than  a 
standard  prepared  as  follows:  to  1  ml.  of  a  solu- 
tion containing  5  mg.  of  apomorphine  hydrochlo- 
ride in  100  ml.  of  water  are  added,  successively, 
6  ml.  of  distilled  water,  1  ml.  of  a  1  in  2Q  sodium 
bicarbonate  solution,  and  0.5  ml.  of  iodine  T.S.; 
after  standing  30  seconds  0.6  ml.  of  0.1  N  sodium 
thiosulfate  is  added  and  the  solution  is  diluted  to 
10  ml.  Residue  on  ignition. — A  negligible  residue 
is  obtained  from  200  mg.  of  apomorphine  hydro- 
chloride. Decomposition  products. — Not  more 
than  a  pale  reddish  color  develops  when  100  mg. 
of  apomorphine  hydrochloride  is  shaken  with  5  ml. 
of  ether.    U.S.P. 

The  B.P.  requires'that  the  precipitate  produced 
on  addition  of  sodium  bicarbonate  be  soluble  in 
ether  with  the  production  of  a  purple  solution,  in 
chloroform  to  produce  a  blue  solution  and  in  90 
per  cent  alcohol  to  form  a  green  solution.  The  B.P. 
permits  up  to  5.0  per  cent  loss  of  weight  on  drying 
at  105°.  The  LP.  limits  loss  of  weight  on  drying 
also  to  5.0  per  cent,  but  the  substance  is  dried 
to  constant  weight  in  a  vacuum  desiccator  over 
sulfuric  acid  or  phosphorus  pentoxide. 

Incompatibilities. — Apomorphine  hydrochlo- 
ride forms  precipitates  with  sodium  bicarbonate, 
tannic  acid  and  most  alkaloidal  reagents.  It  is 
incompatible  with  oxidizing  agents,  forming  col- 
ored solutions. 

Aqueous  or  alcoholic  solutions  of  apomorphine 
are  unstable,  gradually  acquiring  a  green  color. 
Amy  (/.  A.  Ph.  A.,  1931,  20,  1153)  has  shown 
that  this  change  is  not  due  to  the  action  of  light; 
it  may  be  prevented  by  replacing  the  air  in  am- 
puls of  the  solution  with  carbon  dioxide.  The 
oxidation  takes  place  more  readily  in  alkaline 
solutions,  and  may  be  retarded  by  the  addition  of 
a  little  hydrochloric  or  acetic  acid.  The  B.P.  adds 
0.1  per  cent  w/v  of  sodium  metabisulfite  to  delay 
decomposition  of  the  official  injection  of  apomor- 
phine hydrochloride.  Solutions  which  have  a 
green  color  are  not  to  be  used. 

Uses. — Apomorphine  hydrochloride  is  a  prompt 
and  efficient  emetic,  producing  results  in  10  to  15 
minutes.  Apomorphine  induces  emesis  through  a 
central  action  only.  Eggleston  and  Hatcher 
(/.  Pharmacol,  1912,  3,  551)  located  the  site 
of  action  at  the  vomiting  center  in  the  medulla, 
but  more  recently  Wang  and  Borrison  {Arch. 
Neurol.  Psychiat.,  1950,  63,  928,  and  Proc.  S.  Exp. 
Biol.  Med.,  1951,  76,  335)  described  a  chemo- 
sensitive  trigger  zone  in  the  floor  of  the  fourth  ven- 
tricle which  is  sensitive  only  to  emetic  chemicals 
and  does  not  respond  as  does  the  previously 
described  vomiting  center  to  electrical  stimula- 
tion. Ablation  of  this  zone  produces  in  dogs  tol- 
erance to  apomorphine  in  doses  as  high  as  1  Gm. 
intravenously  (Gastroenterology,  1952,  22,  1). 

Therapeutic  doses  ordinarily  have  very  little 
other  action  although  in  large  doses,  and  occa- 
sionally in  therapeutic  doses,  it  has  a  hypnotic 
effect  (Rosenwasser,  Med.  Rec,  July,  1907).  At 


times  it  causes  euphoria,  restlessness  and  tremors. 
There  have  been  instances  of  serious  depression 
and  even  death  of  feeble  patients  from  the  use  of 
therapeutic  doses.  Although  very  large  doses  have 
a  depressant  action  on  the  heart,  it  is  probable 
that  these  unfortunate  occurrences  are  due  to 
the  marked  relaxation  of  the  arteries  and  conse- 
quent fall  of  blood  pressure  which  accompanies 
violent  nausea.  Apomorphine  should  not  be  used 
as  an  emetic  in  persons  with  enfeebled  circulation 
such  as  occurs  in  cases  of  corrosive  poisoning  with 
peripheral  vascular  collapse,  or  narcosis  due  to 
opiates,  barbiturates,  ethyl  alcohol,  etc. 

Rovenstine  and  Hershey  (Anesth.,  1945,  6,  574) 
brought  under  control  within  5  to  10  minutes  the 
excessive  central  nervous  system  stimulation  in 
patients  with  emergence  delirium  following  gen- 
eral anesthesia  by  the  slow  intravenous  or  intra- 
muscular administration  of  1.3  to  2  mg.  of 
apomorphine  hydrochloride  in  10  ml.  of  isotonic 
sodium  chloride  solution.  Similar  results  were 
obtained  in  patients  with  excessive  muscular  or 
psychic  activity  due  to  other  causes. 

Apomorphine  hydrochloride  is  useful  in  cases 
of  poisoning  or  any  other  condition  where  it  is 
desired  promptly  to  empty  the  stomach.  Its  ad- 
vantages are  its  lack  of  irritation  of  the  gastric 
mucosa,  the  smallness  of  dose  which  makes  it 
possible  to  carry  it  in  the  form  of  a  hypodermic 
tablet,  and  the  promptness  of  its  effect.  In  cases 
of  narcotic  poisoning,  however,  it  frequently  fails 
to  act  because  of  the  depression  of  the  vomiting 
center.  When  vomiting  does  not  result  from  the 
first  dose,  it  should  not  be  repeated.  In  doses  too 
small  to  act  as  an  emetic,  it  is  a  nauseating 
expectorant  in  the  early  stages  of  acute  bronchitis. 
One  drawback  to  its  wider  use  for  this  purpose  is 
its  instability  in  solution.  White  (Am.  J.  Obst. 
Gynec,  1952,  64,  91)  found  apomorphine  in 
combination  with  scopolamine  useful  in  producing 
analgesia  and  amnesia  during  labor.  Subcuta- 
neous doses  of  0.6  to  1.2  mg.  appeared  to  poten- 
tiate scopolamine  analgesia  and  the  combined 
drugs  decreased  the  need  for  inhalation  anesthesia. 
No  untoward  effects  were  observed. 

Apomorphine  hydrochloride  is  best  used  hypo- 
dermically;  orally,  its  emetic  action  is  not  de- 
pendable and  from  3  to  5  times  the  hypodermic 
dose  is  required.  Nor  is  oral  administration  suit- 
able for  the  "conditioned  reflex"  method  of  treat- 
ing alcoholism  (Quart.  J.  Stud.  Alcohol,  1940,  1, 
501).  It  is  absorbed  sublingually  (Walton, 
J.A.M.A.,  1944,  124,  139),  the  emetic  dose 
being  from  6.5  to  10  mg.  (approximately  Vio  to  Vs 
grain),  [v] 

The  usual  dose,  subcutaneously,  is  5  mg.  (ap- 
proximately Yn  grain)  with  a  range  of  1  to  5  mg. ; 
the  maximum  safe  dose  is  5  mg.  and  the  total 
dose  in  24  hours  should  seldom  exceed  10  mg. 
The  emetic  dose  for  an  infant  is  1  mg.  (approxi- 
mately Y60  gr.)  hypodermically  or  3  to  5  mg. 
orally  (J. A.M. A.,  1944,  124,  138).  As  an  expec- 
torant, 1  to  2  mg.  has  been  used  subcutaneously. 

Storage. — Preserve  "in  small,  tight,  fight-re- 
sistant vials  containing  not  more  than  350  mg. 
The  restriction  of  350  mg.  applies  only  to  con- 
tainers from  which  prescriptions  are  filled."  U.S.P. 


Part  I 


Aprobarbital  103 


INJECTION    OF   APOMORPHINE 
HYDROCHLORIDE.     B.P.,  I.P. 

Injectio  Apomorphinae  Hydrochloridi 

This  injection  is  a  sterile  solution  of  apomor- 
phine  hydrochloride  in  water  for  injection;  it 
contains  also  0.1  per  cent  w/v  of  sodium  meta- 
bisulfite.  The  solution  is  sterilized  by  heating  with 
a  bactericide  (0.2  per  cent  w/v  of  chlorocresol 
or  0.002  per  cent  w/v  of  phenylmercuric  nitrate 
in  the  solution)  to  maintain  a  temperature  of 
98°  to  100°  for  30  minutes,  or  by  filtration 
through  a  bacteria-proof  filter.  B.P.  The  I.P.  em- 
ploys 0.05  per  cent  of  sodium  pyrosulfite  (meta- 
bisulfite).  Neither  pharmacopeia  provides  an  as- 
say rubric. 

The  injection  should  be  protected  from  light; 
it  may  decompose  on  standing  and  if  a  green 
color  develops  the  solution  should  be  rejected. 

APOMORPHINE  HYDROCHLORIDE. 
TABLETS.     U.S.P. 

[Tabellae  Apomorphinae  Hydrochloridi] 

"Apomorphine  Hydrochloride  Tablets  contain 
not  less  than  90  per  cent  and  not  more  than  110 
per  cent  of  the  labaled  amount  of  C17H17NO2.- 
HC1.^H20."  U.S.P. 

Sp.  Tabletas  de  Clorhidrato  de  Apomorfina. 

Assay. — A  representative  sample  of  powdered 
tablets,  equivalent  to  about  50  mg.  of  apomor- 
phine hydrochloride,  is  dissolved  in  water  and, 
after  adding  sodium  bicarbonate,  extracted  with 
peroxide-free  ether  to  remove  the  apomorphine. 
After  washing  the  combined  ether  extracts  20  ml. 
of  0.02  N  sulfuric  acid  is  added  and  the  mixture 
agitated  thoroughly;  the  excess  of  acid  in  the 
aqueous  phase  is  titrated  with  0.02  N  sodium  hy- 
droxide, using  methyl  red  T.S.  as  indicator.  Each 
ml.  of  0.02  N  sulfuric  acid  represents  6.256  mg.  of 
Ci7Hi7N02.HCl.^H20.   U.S.P. 

Storage. — Preserve  "in  well-closed  contain- 
ers." U.S.P. 

Usual  Size. — 5  mg.  (approximately  Vvi  grain). 

APROBARBITAL.     N.F. 

Allylisopropylbarbituric   Acid,    Allylisopropylmalonyurea 


{C^2 


CH2CH=CH2 


Alurate  (Hoffmann-LaRoche) . 

Aprobarbital,  which  is  5-allyl-5-isopropylbar- 
bituric  acid,  may  be  prepared  either  by  treating 
isopropylbarbituric  acid  with  allyl  halide  at  low 
temperature,  according  to  German  Patent  539,806 
(1920),  or  by  heating  isopropylallylmalonic  acid 
with  urea  in  the  presence  of  sodium  alcoholate, 
acidification  of  the  product  yielding  the  free  acid, 
according  to  Swiss  Patent  167,802  (1934). 

Description. — "Aprobarbital  occurs  as  a  fine, 
white,  odorless  crystalline  powder  having  a 
slightly  bitter  taste.  It  is  stable  in  air.  A  saturated 
solution  is  acid  to  litmus  paper.  Aprobarbital  is 
very  slightly  soluble  in  cold  water  and  is  soluble 


in  alcohol,  in  chloroform,  and  in  ether.  Apro- 
barbital melts  between  140°  and  141.5°."  N.F. 

Standards  and  Tests. — Identification. — Tests 
(1)  and  (2)  are  practically  identical  with  iden- 
tification tests  (1)  and  (2)  under  Barbital  and 
Cyclobarbital,  while  test  (3)  is  the  same  as  iden- 
tification test  (3)  under  Cyclobarbital.  Loss  on 
drying. — Not  over  1  per  cent,  when  dried  at  105° 
for  2  hours.  Residue  on  ignition. — Not  over  0.1 
per  cent.  Readily  carbonizable  substances. — A 
solution  of  500  mg.  of  aprobarbital  in  5  ml.  of 
sulfuric  acid  has  no  more  color  than  matching 
fluid  A.  N.F. 

Aprobarbital  Sodium. — The  sodium  deriva- 
tive of  aprobarbital  is  not  officially  recognized 
but  it  is  included  in  N.N.R.,  where  it  is  described 
as  a  white,  microcrystalline,  hygroscopic,  odorless 
powder  with  a  slightly  bitter  taste.  It  is  very 
soluble  in  water,  very  slightly  soluble  in  alcohol, 
and  practically  insoluble  in  ether.  Aqueous  solu- 
tions of  aprobarbital  sodium  are  alkaline  to  litmus. 
The  N.N.R.  states  that  the  uses  of  aprobarbital 
sodium  are  the  same  as  those  of  aprobarbital. 
The  soluble  sodium  salt  is  intended  for  oral  or 
rectal  administration,  particularly  as  preanesthesia 
medication;  it  may  also  be  used  in  other  cases  in 
which  large  individual  doses  are  required. 

Uses. — According  to  the  classification  by  Fitch 
and  Tatum  (/.  Pharmacol.,  1932,  44,  325)  apro- 
barbital is  regarded  as  having  intermediate  dura- 
tion of  action  (see  article  on  Barbiturates,  in 
Part  II,  for  general  discussion).  It  is  longer  act- 
ing than  amobarbital,  but  shorter  than  barbital 
(Tatum,  Physiol.  Rev.,  1939,  19,  472).  Actually 
the  actions  and  uses  of  aprobarbital  are  similar 
to  those  of  barbital  but  it  is  more  active,  hence 
the  dosage  is  smaller. 

Aprobarbital  has  been  reported  to  reduce  the 
convulsive  threshold  to  epileptogenic  stimuli,  as 
does  phenobarbital  and  phenylhydantoin  (Barany, 
Arch,  internat.  pharmacodyn.  therap.,  1947,  74, 
155).  It  is  useful  for  general  mild  sedation,  when 
it  is  administered  orally.  Aprobarbital  has  been 
reported  to  be  useful  as  a  rectal  analgesic  agent 
during  labor,  the  sodium  derivative  being  used 
for  this  purpose.  Graham  and  Pettit  {Am.  J.  Obst. 
Gyn.,  1938,  35,  1023)  reported  that  when  ad- 
ministered in  this  manner  they  were  able  to  pro- 
duce amnesia  in  67  per  cent  of  cases  and  partial 
amnesia  in  an  additional  22  per  cent.  However,  it 
tended  to  prolong  duration  of  labor  2  to  5  hours. 
Hauch  {Acta  obst.  et  gynec.  Scandinav.,  1938,  18, 
164)  previously  had  employed  the  drug  as  a  basal 
amnesic  agent  in  normal  deliveries,  and  Huard 
et  al.  {Rev.  med.  franc,  d' Extreme-Orient.,  1938, 
16,  279)  attested  to  intravenous  use  of  the  so- 
dium derivative  preoperatively  for  basal  sedation. 

Apparently  the  fairly  long  duration  of  sedation 
produced  by  aprobarbital  is  due  to  its  slow  elimi- 
nation by  excretion  and  by  degradation.  Maynert 
and  Van  Dyke  {Pharmacol.  Rev.,  1949,  1,  217) 
quote  available  literature  to  the  effect  that  the 
compound  is  excreted  by  man  to  the  extent  of 
13  to  24  per  cent  of  a  single  dose.  Following  re- 
peated administration  it  may  continue  to  be 
excreted  in  urine  for  3  to  5  days.  Masson  and 
Beland  {Anesthesiology,  1945,  6,  483)  reported 
that  aprobarbital  is  partially  metabolized,  mainly 


1 04  Aprobarbital 


Part  I 


in  the  liver.  While  the  compound  has  not  been 
found  to  be  particularly  toxic,  Hoick  et  al.  (J.  A. 
Ph.  A.,  1950,  39,  630)  reported  development  of 
tolerance  to  aprobarbital  and  cross-tolerance  to 
Nostal.  Jurgens  (Arch.  exp.  Path.  Pharm.,  1951, 
212,  440)  found  that  this  drug  did  not  produce 
any  blood  dyscrasias  when  administered  to  rabbits. 

Dose. — For  mild  sedation,  60  mg.  (approxi- 
mately 1  grain)  of  aprobarbital  at  bedtime;  in 
obstinate  cases  130  mg.  may  be  administered. 
For  preoperative  use  the  average  dose,  commonly 
of  the  sodium  derivative,  is  10  mg.  per  Kg.  of 
body  weight.  One-third  of  the  calculated  dose  is 
administered  orally  10  to  12  hours  (or  the  eve- 
ning) before  surgery;  the  remainder  being  given 
2  hours  before  the  operation.  Since  this  is  a  large 
dose,  care  and  judgment  must  be  exercised  in  its 
use  to  avoid  undesirably  heavy  sedation. 

Storage. — Preserve  "in  well-closed  contain- 
ers." N.F. 

ARALIA.     N.F. 

American  Spikenard,  Spignet,   [Aralia] 

"Aralia  consists  of  the  dried  rhizome  and  roots 
of  Aralia  racemosa  Linne  (Fam.  Araliacece) ." 
N.F. 

American  Spikenard  is  a  perennial  herb  with 
several  widely  branched,  unarmed,  aerial  stems 
which  arise  to  the  height  of  1  to  1.8  meters  and 
bear  ternately  to  quinately  compound  leaves, 
each  with  broadly  ovate  leaflets  having  acumi- 
nate apices,  cordate  bases  and  doubly  serrate 
margins.  The  flowers  are  small,  greenish-yellow, 
and  borne  on  panicles  of  umbels.  The  fruits  are 
sub-globular,  dark  purplish  to  reddish-brown 
berries.  It  is  indigenous  to  eastern  North  Amer- 
ica west  to  Minnesota  and  Missouri.  The  rhi- 
zomes and  roots  are  collected  in  summer  and 
autumn,  cut  into  segments,  the  thicker  rhizomes 
cut  lengthwise  and  all  carefully  dried.  Most  of 
the  commercial  drug  comes  from  Indiana,  Mis- 
souri, North  Carolina,  Virginia,  Washington  and 
Illinois. 

Description. — "Unground  Aralia. — The  rhi- 
zome of  Aralia  is  oblique,  about  12  cm.  long  and  5 
cm.  thick,  somewhat  flattened,  tortuous,  externally 
weak  brown  to  weak  yellowish  orange,  often  scaly, 
somewhat  annulately  roughened,  frequently  cut 
longitudinally,  and  lighter-colored  internally.  The 
nodes  are  approximate,  each  having  a  prominent 
stem-scar  about  3  cm.  in  width.  The  fracture  is 
fibrous.  Roots  are  numerous,  of  varying  length 
and  up  to  25  mm.  thick;  externally  furrowed, 
sometimes  with  transverse  ridges  and  corky 
patches,  pale  red-purple  to  weak  yellowish  orange, 
usually  cut  longitudinally,  the  cut  surfaces  lighter- 
colored  and  spongy.  The  fracture  of  the  cortex  is 
short  and  of  the  wood  short-fibrous.  Aralia  has 
an  aromatic  odor  and  a  mucilaginous,  pungent, 
and  slightly  acrid  taste."  N.F.  For  histology  see 
N.F.X. 

"Powdered  Aralia  is  light  yellowish  brown.  The 
starch  grains  are  simple  or  compound,  spherical 
or  angular,  from  5  to  25  n  in  diameter.  The  ro- 
settes of  calcium  oxalate  are  from  30  to  70  n 
in  diameter.  The  vessels  have  sclariform  or  reticu- 
late   thickenings    and    simple    or    bordered    pits. 


The  powder  also  shows  characteristic  lignified 
cells  from  the  hypodermis,  40  to  100  n  in  length 
and  about  one-half  as  broad,  their  walls  showing 
simple  pits  (distinction  from  Aralia  nudicaulis 
root)."   N.F. 

Closely  allied  to  the  official  species,  both  bo- 
tanically  and  therapeutically,  are  the  A.  nudi- 
caulis L.  (American,  False  or  Wild  Sarsaparilla 
or  Shot-bush)  and  the  A.  spinosa  L.  (Angelica 
Tree,  Hercules  Club  or  Prickly  Elder) .  The  latter 
has  sometimes  been  referred  to,  improperly,  as 
"prickly  ash"  and  has  occurred  as  an  adulterant 
of  the  true  prickly  ash,  Xanthoxylum  Ameri- 
canum. 

There  appear  to  be  no  published  reports  of  a 
phytochemical  study  of  A.  racemosa  but  Holden 
(Am.  J.  Pharm.,  1880)  found  in  A.  spinosa  a 
saponin  to  which  he  gave  the  name  of  araliin.  It 
is  probable  that  the  official  species  owes  whatever 
medicinal  virtue  it  may  possess  to  the  presence 
of  a  small  amount  of  a  volatile  oil. 

Standards  and  Tests. — Aralia  contains  not 
more  than  5  per  cent  of  attached  stem-bases,  nor 
more  than  2  per  cent  of  foreign  organic  matter 
other  than  stem-bases,  and  yields  not  more  than 
2  per  cent  of  acid-insoluble  ash.  AT.F. 

Uses. — Aralia  has  been  used,  especially  in  do- 
mestic practice,  as  an  "alterative"  similar  to 
sarsaparilla.  in  the  treatment  of  rheumatic,  syphi- 
litic and  cutaneous  affections.  In  medical  practice 
it  was,  at  one  time,  occasionally  employed  in 
pectoral  complaints  but  now  is  no  longer  pre- 
scribed. Its  therapeutic  value  is  extremely  ques- 
tionable and  it  is  official  only  because  it  is  an 
ingredient  of  the  compound  white  pine  syrup. 

The  N.F.  assigns  an  average  dose  of  2  Gm. 
(approximately  30  grains). 

Off.  Prep. — Compound  White  Pine  Syrup. 
N.F. 

ARECA.     N.F. 

Areca  Nut,  Betel  Nut,  [Areca] 

"Areca  is  the  dried  ripe  seed  of  Areca  Catechu 
Linne  (Fam.  Palmce).  Areca  yields  not  less  than 
0.35  per  cent  of  ether-soluble  alkaloids  calculated 
as  arecoline."  N.F. 

Betel  Xut;  Areca  Nut;  Areca  Seed.  Semen  Areca:. 
Fr.  Arec;  Noix  d'arec.  Ger.  Arekasamen ;  Arekanusz; 
Pinangnusz. 

Areca  Catechu  is  a  tall  palm  tree,  reaching  a 
height  of  30  to  50  feet,  indigenous  to  the  Malay 
Archipelago  but  now  cultivated  also  in  India, 
southern  China,  Philippine  Islands  and  East 
Africa.  Its  fruit,  borne  in  pendent  panicles,  is 
ovoid  and  from  2  to  3  cm.  in  diameter,  and  of 
an  orange-yellow  color,  contains  the  seeds  (or 
"nuts")  embedded  in  a  fibrous,  fleshy  envelope, 
and  invested  with  a  brittle  shell  which  adheres 
to  the  exterior  flesh.  The  seed,  the  betel  nut 
of  commerce,  is  of  a  rounded-conical  shape, 
rather  larger  than  a  chestnut,  externally  of  a 
deep  brown,  diversified  with  a  fawn  color,  so  as 
to  present  a  reticulate  appearance,  internally 
brownish-red  with  whitish  veins,  very  hard,  of  a 
feeble  odor  when  broken,  and  of  an  astringent, 
somewhat  acrid  taste. 

Immense  quantities  of  areca  nut  are  consumed 


Part  I 


Arecoline   Hydrobromide  105 


in  the  East.  The  method  used  by  betel  chewers 
consists  of  smearing  fresh  leaves  of  the  Betel- 
pepper  (see  Betel,  Part  II)  with  lime  and  cutch 
and  placing  slices  of  areca  nut  on  the  leaves,  some- 
times with  added  flavoring.  The  entire  mass  is 
placed  in  the  mouth,  acting  as  a  masticatory 
known  by  the  name  of  Betel.  The  red  color  which 
this  mixture  imparts  to  the  saliva  and  the  excre- 
ments is  caused  by  the  areca  nut,  which  is  also 
powerfully  astringent,  and,  by  its  internal  use, 
tends  to  counteract  the  relaxation  of  bowels  to 
which  the  heat  of  the  climate  so  strongly  pre- 
disposes. 

Description. — "Unground  Areca. — Areca  oc- 
curs as  rounded-conical  seeds,  up  to  3.5  cm.  in 
length  and  up  to  3  cm.  in  diameter.  Externally  it 
is  weak  reddish  brown  to  light  yellowish  brown 
and  is  marked  with  a  network  of  paler  lines. 
Adhering  portions  of  the  silvery  brittle  endocarp 
and  fibers  of  the  mesocarp  are  usually  found  at 
the  base  of  the  seed.  The  seed  is  hard,  the  cut 
surface  exhibiting  a  marbled  appearance  (rumi- 
nate endosperm)  of  brownish  tissue  alternating 
with  whitish  tissue.  Areca  has  a  slight  odor  and 
an  astringent,  slightly  bitter  taste."  N.F.  For 
histology  see  N.F.X. 

"Powdered  Areca  is  weak  reddish  brown  to 
light  brown.  It  consists  principally  of  fragments 
of  the  endosperm,  with  porous  reserve-cellulose 
walls,  irregularly  thickened  stone  cells  of  the  seed 
coat,  a  few  aleurone  grains  up  to  40  m.  in  diameter 
and  a  few  oil  globules.  Starch  is  absent,  and  spiral, 
pitted  and  annular  tracheids  and  vessels  are  few." 
N.F. 

Constituents. — Areca  nut  contains  tannin, 
also  gallic  acid,  a  fixed  oil,  gum,  a  little  volatile 
oil,  lignin  and  several  alkaloids.  It  yields  its 
astringency  to  water,  and  in  some  parts  of  Hin- 
dustan an  extract  is  prepared  from  it  having  the 
appearance  and  properties  of  catechu.  A  red 
coloring  matter  known  as  Areca  red  is  extracted, 
probably  resulting  from  the  decomposition  of  a 
tannin.  It  is  insoluble  in  cold  water  and  ether, 
soluble  in  boiling  water  and  alkaline  liquids,  from 
which  it  is  precipitated  by  acids. 

From  the  seeds  of  areca  Jahns  isolated,  in  1888, 
the  alkaloids  arecoline,  arecaidine,  arecaine  and 
gavacaine;  the  second  and  third  of  these  have 
been  shown  to  be  identical.  To  these  have  been 
added  arecolidine,  guvacoline  and,  possibly,  a 
sixth  alkaloid  called  isoguvacine.  There  is  some 
basis  for  believing  the  last-named  to  be  mainly 
arecaidine.  Arecoline  has  been  shown  to  be  the 
methyl  ester  of  arecaidine,  and  the  latter  has 
been  identified  and  synthesized  as  1  -methyl- A3- 
tetrahydropyridine-3-carboxylic  acid.  Guvacoline 
is  now  known  to  be  the  methyl  ester  of  guvacine ; 
this,  too,  has  been  identified  and  synthesized  as 
A3-tetrahydropyridine-3-carboxylic  acid.  For  a 
further  discussion  of  these  alkaloids  see  Henry 
{Plant  Alkaloids,  4th  ed.,   1949). 

Standards  and  Tests. — Areca  contains  not 
more  than  2  per  cent  of  adhering  pericarp,  nor 
more  than  1  per  cent  of  foreign  organic  matter, 
and  yields  not  over  2.5  per  cent  of  ash.  N.F. 

Assay. — A  sample  of  8  Gm.  of  areca,  in  mod- 
erately coarse  powder,  is  macerated  with  ether 
and  ammonia;  an  aliquot  representing  5  Gm.  of 


drug  is  decanted  after  clarification,  and  most  of 
the  ether  distilled  off.  The  alkaloids  in  the  con- 
centrated ethereal  solution  are  extracted  with 
15  ml.  of  0.02  N  sulfuric  acid  and  the  excess  acid 
titrated  with  0.02  N  sodium  hydroxide,  using 
methyl  red  T.S.  as  indicator.  Each  ml.  of  0.02  N 
sulfuric  acid  represents  3.104  mg.  of  alkaloids 
calculated  as  arecoline.  N.F. 

Uses. — Areca  nut  owes  its  therapeutic  uses 
almost  entirely  to  the  alkaloid  arecoline,  the  other 
bases  which  it  contains  being  relatively  inert. 
For  description  of  its  effects  see  under  Arecoline 
Hydrobromide. 

This  drug  is  so  far  as  we  know,  almost  never 
used  in  human  medicine  but  is  employed,  as  a 
vermifuge,  by  veterinarians.  Its  use  in  veterinary 
medicine  is  described  in  Part  III.  The  N.F.  gives 
the  dose  for  dogs  as  2  to  4  Gm.  (approximately 
30  to  60  grains)  and  for  sheep  as  4  to  8  Gm. 
(approximately  1  to  2  drachms)  depending  on  the 
weight  of  the  animal. 


ARECOLINE  HYDROBROMIDE.     N.F. 

Arecolinium  Bromide,   [Arecolinae  Hydrobromidum] 

"Arecoline  Hydrobromide  is  the  hydrobromide 
of  an  alkaloid  obtained  from  the  dried  ripe  seed 
of  Areca  Catechu  Linne  (Fam.  Palmaz)  or  pro- 
duced synthetically."  N.F. 

Arecolinum  Hydrobromicum;  Arecolinae  Bromhydras. 
Fr.  Bromhydrate  d'arecoline.  Ger.  Arekolinhydrobromid. 
Sp.  Bromhidrato  de  arecolina. 

This  alkaloid,  discovered  by  Jahns  in  1888, 
is  obtained  from  areca  nut  (betel  nut),  which 
contains  0.3  to  0.6  per  cent  of  arecoline. 
In  a  commercial  process  for  preparing  arecoline 
the  powdered  drug  is  extracted  with  alcohol,  the 
solvent  evaporated  under  vacuum,  the  syrupy 
residue  dissolved  in  carbon  tetrachloride  and  this 
solution  extracted  with  dilute  sulfuric  acid,  which 
removes  the  arecoline.  The  alkaloid  may  then  be 
separated  from  the  aqueous  solution  by  alkaliniz- 
ing  it  and  extracting  with  chloroform.  The  hydro- 
bromide provides  the  most  suitable  means  for 
purifying  the  alkaloid  by  recrystallization. 

Arecoline  has  been  synthesized  by  several  dif- 
ferent methods.  Mannich  (Ber.,  1942,  75B,  1480) 
prepared  it  starting  with  methylamine  hydrochlo- 
ride, formaldehyde,  acetaldehyde  and  water.  Dan- 
kova  et  al.  (see  Chem.  Abs.,  1943,  37,  381)  de- 
scribed what  is  said  to  be  a  commercially  feasible 
synthesis  starting  with  ethylene  oxide  (see  also 
Ugryumov,  Chem.  Abs.,  1941,  35,  3644). 

Arecoline  has  the  structure  of  methyl  1,2,5,6- 
tetrahydro-1-methylnicotinate;  it  is  a  partially 
hydrogenated  nicotinic  acid  derivative.  The  base 
is  an  oily,  strongly  alkaline,  optically  inactive 
liquid,  boiling  at  about  209°.  It  is  miscible  with 
water,  ether  or  chloroform  and  is  volatile  with 
steam. 

Description. — "Arecoline  Hydrobromide  oc- 
curs as  a  white,  crystalline  powder,  or  in  the  form 
of  white  crystals.  It  is  odorless  and  has  a  bitter 
taste.  It  is  affected  by  light.  One  Gm.  of  Areco- 
line Hydrobromide  dissolves  in  about  1  ml.  of 
water,  in  about  10  ml.  of  alcohol,  and  in  about 
2  ml.  of  boiling  alcohol.  It  is  slightly  soluble  in 


106  Arecoline    Hydrobromide 


Part   I 


ether  or  chloroform.  Arecoline  Hydrobromide 
melts  between  170°  and  175°."  N.F. 

Standards  and  Tests. — Identification. — (1) 
A  1  in  20  solution  of  arecoline  hydrobromide  re- 
sponds to  tests  for  bromide.  (2)  A  red-brown 
precipitate  forms  on  adding  iodine  T.S.  to  a  1  in 
50  solution  of  arecoline  hydrobromide;  a  yellow 
precipitate  is  produced  by  bromine  T.S.  Loss  on 
drying. — Not  over  1  per  cent,  when  dried  at  80° 
for  2  hours.  Ash. — Not  over  0.5  per  cent.  Acidity. 
— Not  over  0.2  ml.  of  0.1  N  sodium  hydroxide  is 
required  to  neutralize  500  mg.  of  arecoline  hydro- 
bromide, using  methyl  red  T.S.  as  indicator.  Sul- 
fate.— No  turbidity  or  precipitate  forms  in  30 
seconds  when  1  ml.  of  barium  chloride  T.S.  is 
added  to  10  ml.  of  a  1  in  100  solution  of  areco- 
line hydrobromide,  acidulated  with  5  drops  of 
diluted  hydrochloric  acid.  Other  alkaloids. — No 
precipitate  or  turbidity  is  produced  when  ammo- 
nia T.S.  or  sodium  hydroxide  T.S.  is  added  to  a 
1  in  20  solution  of  arecoline  hydrobromide  (areco- 
line base  is  soluble  in  water).  N.F. 

In  a  study  of  the  stability  of  aqueous  solutions 
of  arecoline  hydrobromide  on  sterilization,  Schou 
(Dansk  Tids.  Farm.,  1936,  10,  175)  found  that 
no  hydrolysis  occurred  after  heating  for  one  hour 
at  100°  but  that  autoclaving  for  20  minutes 
at  120°  decomposed  5  per  cent  of  the  areco- 
line. He  found  that  solutions  of  the  salt  are 
stabilized  by  the  addition  of  small  amounts  of 
hydrochloric  acid. 

Uses. — Arecoline  closely  resembles  pilocarpine 
in  physiological  action,  both  drugs  stimulating 
structures  innervated  by  postganglionic  nerves 
(see  the  monograph  in  Part  II  on  Parasympatho- 
mimetic Agents  and  Cholinesterase  Inhibitors). 
Arecoline  causes  a  marked  increase  of  secretions, 
especially  of  the  salivary  gland,  contraction  of 
the  pupil  when  instilled  into  the  eye,  increased 
intestinal  peristalsis,  constriction  of  bronchi,  and 
a  slowing  of  the  heart  and  vasodilatation  with 
resulting  fall  in  blood  pressure  (Platz,  Ztschr. 
exp.  Path.  Ther.,  1910,  7;  Jackson,  /.  Pharmacol., 
1914,  5,  479).  Mentova  (Farmakol.  i  Toksikol., 
1940,  3,  1)  observed  constriction  of  the  coronary 
arteries  in  rabbits  following  administration  of 
arecoline,  acetylcholine  or  physostigmine. 

Arecoline  has  been  employed  to  a  small  extent 
in  the  treatment  of  glaucoma.  A  1  per  cent  solu- 
tion produces  a  marked  reduction  in  the  intra- 
ocular tension,  but  its  effects  are  more  transient 
than  those  of  pilocarpine  or  physostigmine.  It 
may  cause  considerable  irritation  of  the  cornea 
but  apparently  does  not  injure  the  continuity  of 
the  epithelium. 

Arecoline  is  a  very  potent  taeniacide  and  ap- 
parently is  also  poisonous  to  the  roundworm, 
but,  according  to  Schueffner,  has  no  influence  on 
the  hookworm  (Arch.  Schiffs-Tropen-Hyg.,  1912, 
16,  569).  Because,  however,  of  its  toxic  systemic 
action  it  has  been  abandoned  in  human  medicine 
but  is  still  used  by  veterinarians,  (v] 

Toxicology. — Excessive  doses  cause  saliva- 
tion, vomiting,  diuresis,  coma  and  convulsions 
(Wachholz,  Ztschr.  ges.  gerichtl.  Med.,  1932,  19, 
224).  If  ingested,  gastric  lavage  and  use  of  po- 
tassium  permanganate    are   indicated.    Atropine 


sulfate  parenterally  may  minimize  the  effects  of 
strong  parasympathetic  stimulation.  The  N.F. 
gives  a  dose  lor  horses  of  30  mg.  (approximately 
^2  grain)  subcutaneously  and  for  dogs  of  1.5  mg. 
per  kilogram  of  body  weight  (approximately  %d 
grain  per  pound). 

Storage. — Preserve  in  "tight,  light-resistant 
containers."  N.F. 

ARECOLINE  HYDROBROMIDE 
TABLETS.  N.F. 

[Tabellae  Arecolinae  Hydrobromidi] 

"Arecoline  Hydrobromide  Tablets  contain  not 
less  than  91  per  cent  and  not  more  than  109  per 
cent  of  the  labeled  amount  of  CsHisNCte.HBr." 
N.F. 

Assay. — Not  less  than  20  tablets  are  allowed  to 
disintegrate  in  distilled  water,  the  mixture  diluted 
to  200  ml.,  filtered,  and  an  aliquot  portion  equiva- 
lent to  about  0.3  Gm.  of  arecoline  hydrobromide 
assayed  by  the  Volhard  method  for  bromide  con- 
tent by  adding  a  measured  excess  of  0.1  N  silver 
nitrate  and  some  nitric  acid  and  titrating  the  ex- 
cess of  silver  nitrate  with  0.1  TV  ammonium  thio- 
cyanate  using  ferric  ammonium  sulfate  T.S.  as 
indicator.  Each  ml.  of  0.1  N  silver  nitrate  repre- 
sents 23.61  mg.  of  C8Hi3N02.HBr.  N.F. 

Usual  Sizes. — 8,  15.  30  and  60  mg.  (approxi- 
mately %,  x/i,  Yz  and  1  grain). 

ARNICA.     N.F. 

Arnica  Flowers,  [Arnica] 

"Arnica  consists  of  the  dried  flower  head  of 
Arnica  montana  Linne,  known  in  commerce  as 
European  Arnica  or  of  Arnica  fulgens  Pursh, 
Arnica  sororia  Greene  and  Arnica  cordi folia 
Hooker,  known  in  commerce  as  American  Arnica 
(Fam.  Compositor)"  N.F. 

Wolf's  Bane;  Mountain  Tobacco.  Flores  Arnica.  Fr. 
Arnica;  Fleurs  d'araica.  Ger.  Arnikabliiten;  Bergwurzel- 
blumen;  Blutblumen;  Engelblumen ;  Gamsblumen.  It. 
Arnica;  Fiori  di  arnica.  Sp.  Arnica. 

Arnica  montana  L.  is  a  perennial  herb  having 
a  woody,  brownish,  horizontal  rhizome,  from  2 
to  10  cm.  long,  and  0.5  to  5  mm.  thick,  ending 
abruptly,  and  sending  forth  numerous  slender 
fibers  of  the  same  color.  The  stem  is  up  to  6  dm. 
in  height,  cylindrical,  striated,  glandular-hairy, 
and  terminating  in  one,  two,  or  three  peduncles, 
each  bearing  a  flower  head.  The  radical  leaves  are 
oblanceolate,  entire  and  ciliated;  those  of  the 
stem,  which  usually  consist  of  two  opposite  pairs, 
are  elliptic  oblong  or  lance-shaped.  Both  are 
bright  green,  and  somewhat  pubescent  on  their 
upper  surface.  The  flower  heads  are  orange-yellow. 

This  plant  is  a  native  of  the  mountains  and 
meadows  of  Europe.  It  has  been  introduced  into 
England,  and  cultivated  in  northern  gardens  in  the 
United  States.  The  flowers,  leaves  and  root  are 
employed;  but  the  flowers  only  are  official.  In 
the  Swiss  and  German  Pharmacopoeias  the  defini- 
tion of  arnica  flowers  is  restricted  to  the  flowers 
separated  from  the  receptacles,  this  being  done 
as  the  latter  contain  the  eggs  or  larvae  of  Trypeta 
arnicivora.  On  the  other  hand  the  Austrian  Phar- 
macopoeia permits  the  use  of  the  entire  flower 


Part  I 


Arnica 


107 


heads,  but  the  receptacles  containing  larvae  must 
be  removed. 

The  American  species  of  Arnica  recognized  by 
the  N.F.  are  Arnica  fulgens,  A.  sororia  and  A, 
cordifolia.  All  of  them  are  glandular-hairy,  per- 
ennial herbs  with  slender  horizontal  rhizomes  bear- 
ing basal  rosettes  of  radical  leaves  from  the 
centers  of  which  arise  one  or  more  aerial  stems 
bearing  from  1  to  3  peduncles  which  terminate 
in  showy  flower  heads  of  yellow  to  orange  {A. 
julgens)  ray  and  disk  florets.  A.  julgens  and  A. 
sororia  are  native  to  southwestern  Canada  and 
western  United  States.  A.  cordifolia  has  a  range 
from  Alaska  down  the  Rocky  Mountains  to  New 
Mexico  and  Arizona,  in  the  Sierra  and  Cascade 
ranges  south  to  San  Diego  County,  California. 

Arnica  julgens  Pursh  or  orange  arnica  is  espe- 
cially characterized  by  possessing  dense  tufts  of 
tawny  hairs  in  the  axils  of  the  bases  of  its  radical 
leaves  of  previous  years  which  are  attached  to  the 
rhizome,  by  its  aerial,  puberulent,  glandular-hairy 
stem  bearing  from  4  to  6  pairs  of  cauline  leaves, 
the  upper  pairs  reduced  and  separated  by  a  long 
internode  from  the  lower  pairs  which  are  oblance- 
olate,  entire  or  with  a  few  teeth  and  by  its  flower 
head  of  dark  orange  to  orange  flowers. 

A.  sororia  Greene  somewhat  resembles  the  last 
species  but  its  rhizome  is  less  than  half  as  thick 
with  few  or  no  tufts  of  hairs  in  the  axils  of  the 
old  attached  radical  leaves,  its  aerial  stem  bears 
4  to  5  pairs  of  cauline  leaves,  the  two  to  three 
pairs  near  the  base  being  oblanceolate,  and  its 
flower  head  bears  yellow  ray  and  disk  florets. 

A.  cordifolia  Hooker  or  heart  leaf  arnica  is  char- 
acterized by  having  2  to  4  pairs  of  cauline  leaves, 
the  basal  and  lower  leaves  being  petiolate  with 
slender,  sometimes  margined  petioles  as  long  as  or 
exceeding  the  lamina,  the  latter  varying  from 
ovate  to  ovate-orbicular,  cordate  or  lanceolate 
with  cordate  to  truncate  base  and  entire  to 
coarsely  toothed  margin.  Its  flower  heads  are 
broadly  turbinate  to  bell-shaped  with  yellow  ray 
and  disk  florets.  Its  involucral  bracts  differ  from 
those  of  the  preceding  species  in  being  frequently 
irregularly  toothed  to  laciniate  along  the  margins. 
For  details  on  the  official  Arnica  yielding  species 
and  the  gross  structure  and  histology  of  their 
flower  heads  see  the  report  of  Youngken  and 
Wirth,  /.  A.  Ph.  A.,  1945,  34,  65. 

The  flower  heads  of  arnica  are  collected  when 
fully  expanded,  the  florets  of  European  arnica 
being  usually  separated  from  their  receptacles  and 
carefully  dried.  American  arnica  flower  heads  are 
dried  intact.  European  arnica  has  been  imported 
into  the  U.  S.  A.  from  Germany,  Belgium,  Yugo- 
slavia, France  and  Italy.  American  arnica  is  being 
collected  chiefly  in  the  Rocky  Mountain  states, 
especially  Montana  and  Wyoming,  and  also  in 
the  Dakotas. 

Description. — "Unground  Arnica  occurs  as 
entire  flower  heads  or  as  tubular  and  ligulate 
florets  usually  with  some  receptacles  and  invo- 
lucres. The  heads  are  either  hemispherical,  tur- 
binate, or  campanulate,  up  to  2.8  cm.  in  height. 
The  receptable  is  flat  to  slightly  convex  (Arnica 
montana)  or  prominently  convex  (American 
Arnicas),  deeply  pitted,  and  covered  with  short 


hairs.  The  involucral  bracts  are  lanceolate  to 
elliptic  oblong,  those  of  A.  cordifolia  being  fre- 
quently toothed  or  laciniate  along  the  margins, 
light  olive-green  to  weak  reddish  brown,  puberu- 
lent and  glandular-hairy,  up  to  25  mm.  in  length 
and  from  1  to  3.5  mm.  in  width.  The  ligulate 
florets  are  yellow  to  moderate  orange,  pistillate, 
the  ligulate  corolla  being  up  to  27  mm.  in  length, 
up  to  6  mm.  in  width,  its  ligule  usually  3-toothed 
and  7-  to  12-nerved.  The  tubular  florets  are  per- 
fect, goblet-shaped,  yellow  to  yellowish  orange, 
their  stamens  bearing  2  oblong-elliptic  anther 
lobes  united  by  an  elongated  triangular  connective. 
The  achenes  are  oblong  to  spindle-shaped,  ap- 
pressed-hispid,  longitudinally  striate  or  dotted, 
3.5  to  7  mm.  in  length,  brownish  gray  to  light 
olive-brown,  with  a  collar  near  the  summit  bearing 
a  single  circle  of  barbellate  pappus  bristles,  a 
little  longer  than  the  achene.  The  odor  is  charac- 
teristic and  agreeable. 

"Powdered  Arnica  is  light  yellowish  brown  to 
light  olive-brown.  The  pollen  grains  are  numerous, 
25  to  40  |x  in  diameter,  spheroidal  and  spinose. 
The  non-grandular  hairs  are  of  the  following 
kinds :  unicellular  and  uniseriate-articular,  straight, 
curved  or  dagger-shaped,  the  uniseriate  hairs  up  to 
9-celled,  rarely  11-celled,  some  with  short  basal 
cells  and  elongated  distal  cell,  and  double  hairs, 
the  latter  up  to  384  n  in  length,  mostly  unequal 
in  length  of  parts,  with  bifid  summits,  each  with 
numerous  pits  on  the  dividing  wall  separating 
the  2  components,  one  of  which  is  either  1-  or 
2-celled.  The  glandular  hairs  are  of  the  following 
kinds:  with  a  unicellular  stalk  and  a  1-  to  2-celled 
head;  or  with  a  uniseriate  or  biseriate  stalk  and 
a  1-,  2-,  or  4-celled  head.  The  pappus  bristles 
possess  a  multicellular  axis  and  unicellular 
branches."  N.F. 

Arnica  flowers  of  commerce  are  not  infre- 
quently admixed  with  and  substituted  by  other 
composite  flowers.  Farwell  states  that  the  heads 
of  Lapachis  columnaris  T.  et  G.,  a  western  com- 
posite, have  been  offered  in  large  quantities  for 
arnica.  Hartwich  has  reported  a  sample  of  arnica 
adulterated  with  the  flowers  of  the  common  dan- 
delion. Beilstein  reported  having  found  in  one 
lot  approximately  90  per  cent  of  the  flowers  of 
Inula.  The  following  flowers  also  have  been  used: 
Anthemis  tinctoria,  L.,  Calendula  officinalis,  L., 
Doronicum  Pardalianches,  L.,  Inula  britannica, 
L.,  Scorzonera  humilis,  L.,  Heterotheca  inuloides. 
The  first  three  of  these  are  distinguished  by  the 
fact  that  the  achenes  do  not  have  any  pappus.  In 
Inula  britannica  the  receptacle  is  naked  and  the 
ligulate  flowers  are  four-nerved  (for  other  char- 
acteristics see  Ewing  and  Stitt,  I.  A.  Ph.  A.,  1945, 
34,  151).  In  Scorzonera  the  flowers  are  all  ligulate 
and  the  pappus  is  feather-shaped.  In  Heterotheca 
inuloides  the  florets  have  an  inner  long  pappus 
and  an  outer  short  pappus. 

The  rhizome  (Arnica  Radix)  was  formerly 
official  and  was  described  as  follows : 

"Rhizome  about  5  cm.  long  and  3  or  4  mm. 
thick;  externally  brown,  rough  from  leaf-scars; 
internally  whitish,  with  a  rather  thick  bark,  con- 
taining a  circle  of  resin-cells,  surrounding  the 
short,  yellowish  wood-wedges,  and  large,  spongy 


108 


Arnica 


Part  I 


pith.  The  roots  numerous,  thin,  fragile,  grayish- 
brown,  with  a  thick  bark  containing  a  circle  of 
resin-cells.  Odor  somewhat  aromatic;  taste  pun- 
gently  aromatic  and  bitter."  U.S.P.,  1890. 

It  appears  to  contain  the  same  active  con- 
stituents as  the  flowers. 

Standards. — Arnica  contains  not  more  than 
3  per  cent  of  foreign  organic  matter,  and  not  more 
than  2  per  cent  of  acid-insoluble  ash.  N.F. 

Constituents. — In  1851  Bastick  reported  the 
presence  of  an  alkaloid  in  arnica  flowers  but  his 
findings  have  not  been  confirmed.  The  term 
arnicin  has  been  applied  to  a  variety  of  sub- 
stances which  have  been  extracted  from  arnica 
but  which  are  not  related  and  most,  if  not  all,  of 
which  are  not  pure  principles.  There  is  present 
about  0.5  per  cent  of  a  volatile  oil,  the  most  im- 
portant constituent  of  which  is  the  dimethyl  ether 
of  thymohydroquinone.  For  further  information 
on  this  oil,  see  Kondakow  (/.  pharm.  chim.,  1910, 
2,  79)  and  also  Gildemeister  and  Hoffman,  The 
Volatile  Oils.  There  is  present  also  in  arnica 
flowers  a  colorless  crystalline  substance,  known 
as  arnidiol  or  arnisterin  (Klobb,  Pharm.  Ztg., 
1905,  40,  846),  for  which  Dieterle  and  Engelhard 
Arch.  Pharm.,  1940,  278,  225)  proposed  the  name 
arnidendiol ;  it  is  a  triterpenediol  found  also  in 
dandelion  flowers  {Zimmermann,  Helv.  Chim. 
Acta,  1941,  24,  393).  Small  amounts  of  angelic 
and  formica  acids  have  also  been  reported.  From 
a  petroleum  ether  extract  of  arnica  flowers 
Dieterle  and  Fay  {Arch.  Pharm.,  1939,  277,  65) 
isolated  three  crystalline  substances,  as  yet  in- 
completely identified.  About  56  per  cent  of  this 
extract  consists  of  fatty  acids,  the  composition 
of  which  is  reported  in  their  paper,  along  with 
other  analytical  data  for  the  extract. 

Uses. — Arnica  is  rarely  prescribed  by  physi- 
cians but  has  been  used  in  domestic  medicine  as 
a  counterirritant  embrocation  in  the  treatment  of 
bruises  and  sprains,  generally  in  the  form  of  the 
tincture.  It  has  also  been  used  in  the  treatment 
of  palsies  and  various  other  diseases,  but  little 
knowledge  concerning  its  action  is  available.  Forst 
{Arch.  exp.  Path.  Pharm.,  1943,  201,  242)  re- 
ported that  both  aqueous  and  alcoholic  extracts 
of  A.  montana  contain,  besides  choline,  two  un- 
identified substances  which  affect  the  heart  and 
vascular  systems. 

Toxicology. — Arnica  is  an  active  irritant  and 
is  capable,  when  taken  in  an  overdose,  of  produc- 
ing symptoms  of  violent  toxic  gastroenteritis,  with 
considerable  nervous  disturbance,  reduction  or  in- 
crease of  pulse  rate,  and  collapse.  On  the  skin  it 
may  cause  severe  dermatitis. 

In  a  number  of  cases  of  severe  or  even  fatal 
poisoning  by  arnica,  the  symptoms  have  been 
burning  pains  in  the  stomach,  vomiting,  choleraic 
diarrhea,  giddiness,  intense  muscular  weakness, 
dilated  pupils,  and  finally  complete  insensibility 
and  collapse  (Schoenemann,  Munch,  med.  Wchn- 
schr.,  1938,  85,  787;  Merdinger,  ibid.,  1469; 
Forst,  ibid.,  1939,  86,  145).  In  some  cases  the 
disturbances  of  the  gastrointestinal  tract  have 
been  absent,  and  the  symptoms  have  been  chiefly 
of  cerebral  origin.  An  ounce  of  the  tincture  lias 
produced  serious,  although  not  fatal,  symptoms. 


An  emetic,  a  saline  purge,  demulcent  drinks  and 
supportive  and  symptomatic  measures  are  indi- 
cated for  treatment  of  arnica  poisoning. 

Arnica  flowers  have  been  given  in  a  dose  of  60 
to  200  mg.  (approximately  1  to  3  grains). 

ARNICA  TINCTURE.     N.F. 

[Tinctura  Arnicae] 

Arnica  Flowers  Tincture.  Tinctura  Arnica  Florum. 
Fr.  Teinture  d'arnica.  Ccr.  Arnikatinktur.  It.  Tintura 
di  arnica.  Sp.  Tintura  de  arnica. 

Prepare  a  tincture  by  Process  P  (see  under 
Tinctures),  from  200  Gm.  of  arnica,  in  moderately 
coarse  powder,  using  a  menstruum  of  3  volumes 
of  alcohol  and  1  volume  of  water;  macerate  the 
drug  during  48  hours,  percolate  slowly,  repeat  the 
maceration  during  24  hours  after  500  ml.  of  perco- 
late has  been  collected,  then  percolate  until  1000 
ml.  is  collected.  N.F. 

Alcohol  Content. — From  63  to  69  per  cent, 
by  volume,  of  C2H5OH.  N.F. 

This  tincture  is  sometimes  used  externally  as  a 
mild  counterirritant.  The  N.F.  formerly  assigned 
an  average  dose  of  0.5  ml.  (approximately  8 
minims)  but  it  is  rarely  given  internally  (see 
under  Arnica). 

Storage. — Preserve  "in  tight,  light-resistant 
containers  and  avoid  exposure  to  direct  sunlight 
or  to  excessive  heat."  N.F. 

AROMATIC   ELIXIR.     U.S.P. 

Simple  Elixir,  [Elixir  Aromaticum] 
Sp.  Elixir  Aromdtico. 

To  12  ml.  of  compound  orange  spirit  add 
enough  alcohol  to  make  250  ml.  To  this  solution 
add  375  ml.  of  syrup  in  several  portions,  agitating 
vigorously  after  each  addition;  afterwards  add, 
in  the  same  manner,  enough  purified  water  to 
make  1000  ml.  Mix  30  Gm.  of  talc  with  the 
liquid,  filter  the  mixture  through  a  filter  wetted 
with  diluted  alcohol,  returning  the  filtrate  until  a 
clear  liquid  is  obtained.  U.S.P. 

The  only  difficulty  encountered  in  the  prepara- 
tion of  this  popular  vehicle  is  that  of  obtaining  a 
clear  filtrate,  the  colloidal  dispersion  of  the  drop- 
lets of  volatile  oils  separated  from  compound 
orange  spirit  by  dilution  with  a  large  proportion 
of  water  being  largely  responsible  for  the  persist- 
ing turbidity.  The  high  degree  of  fineness  of  many 
samples  of  talc  is  a  contributing  factor  as  is,  ap- 
parently, also  the  large  proportion  of  syrup  which 
seems  to  delay  flocculation  as  well  as  slow  down, 
because  of  its  viscosity,  the  rate  of  filtration. 
Several  suggestions  have  been  offered  for  im- 
proving the  process — and  the  product — but  none 
of  these  has  been  given  official  recognition.  For  a 
brief  review  of  some  of  the  recommendations  for 
improving  the  formula  see  Saute  and  Lee  {J.  A. 
Ph.  A.,  Prac.  Ed.,  1954,  15,  101),  who  proposed 
a  modification  in  which  a  polyoxyalkalene  nonionic 
solubilizer  {Pluronic,  Wyandotte  Chemical  Corp.) 
is  added  to  the  volatile  oil  component  of  the  elixir 
and  which  avoids  the  need  for  filtering  the  elixir, 
since  it  is  clear. 

Aromatic  elixir,  once  very  widely  used  as  a 


Part  I 


Arsenic 


109 


vehicle,  still  finds  considerable  use  for  this  pur- 
pose ;  it  is  employed  in  the  formulation  of  several 
official  elixirs  and  also  in  Iron  and  Ammonium 
Acetate  Solution. 

Alcohol  Content. — From  21  to  23  per  cent, 
by  volume,  of  C2H5OH.  U.S.P. 

Storage. — Preserve  "in  tight  containers." 
U.S.P. 

RED  AROMATIC  ELIXIR.     N.F. 

Red  Elixir,  Elixir  Aromaticum  Rubrum 

Mix  14  ml.  of  amaranth  solution  with  986  ml. 
of  aromatic  elixir.  N.F. 

Alcohol  Content. — From  21  to  24  per  cent, 
by  volume,  of  C2H5OH.  N.F. 

This  vehicle  is  employed  in  the  same  way  as 
aromatic  elixir,  differing  from  it  only  in  color. 

Storage. — Preserve  "in  tight  containers."  N.F. 

ALKALINE  AROMATIC  SOLUTION 

N.F. 

Liquor  Aromaticus  Alkalinus 
Liquor  Antisepticus  Alkalinus. 

Mix  20  Gm.  each  of  potassium  bicarbonate  and 
sodium  borate  with  100  ml.  of  purified  water  and 
add  100  ml.  of  glycerin;  when  effervescence  ceases 
add  the  mixture  to  500  ml.  of  purified  water.  Dis- 
solve 0.5  Gm.  of  thymol,  1  ml.  of  eucalyptol,  0.5 
ml.  of  methyl  salicylate,  and  14  ml.  of  amaranth 
solution  in  50  ml.  of  alcohol;  add  the  solution  of 
salts  to  the  alcoholic  solution,  agitating  con- 
stantly, and  finally  add  enough  purified  water  to 
make  1000  ml.  Allow  the  mixture  to  stand  24 
hours,  shaking  occasionally,  then  filter,  using  10 
Gm.  of  purified  talc,  if  necessary,  to  clarify  the 
product.  N.F. 

The  effervescence  which  occurs  in  the  prepara- 
tion of  this  solution  is  explained  by  the  fact  that 
sodium  borate,  which  may  be  considered  to  repre- 
sent four  molecules  of  boric  acid  only  half  neutral- 
ized by  two  molecules  of  sodium  bicarbonate,  is 
converted  by  glycerin  to  an  acid-reacting  complex 
capable  of  neutralizing  two  more  molecules  of  an 
alkali  such  as  potassium  bicarbonate.  The  reac- 
tion is  similar  to  that  which  occurs  in  the  prepara- 
tion of  compound  sodium  borate  solution. 

Description. — "Alkaline  Aromatic  Solution  is 
a  clear,  purplish  red  liquid,  with  an  aromatic  odor 
and  taste.  It  is  alkaline  to  litmus  paper.  Its  specific 
gravity  is  about  1.04."  N.F. 

Standard  and  Test. — Residue  on  ignition. — 
The  residue  from  10  ml.  of  alkaline  aromatic  solu- 
tion yields,  on  ignition,  not  less  than  223  mg.  and 
not  more  than  273  mg.  of  residue.  N.F. 

Alcohol  Content. — From  4  to  7  per  cent,  by 
volume,  of  C2H5OH.  N.F. 

Uses. — This  is  a  valuable  substitute  for  a  solu- 
tion of  borax  for  washing  the  nasal  or  pharyngeal 
cavities.  Its  chief  advantages  are  a  mild  alkalinity 
which  helps  to  dissolve  mucus  and  the  fact  that 
when  diluted  with  an  equal  volume  of  water  it  is 
almost  isotonic  with  the  body  fluids.  For  use  in  a 
dental  spray  bottle,  it  is  diluted  with  5  volumes  of 
water. 

Storage. — Preserve  "in  tight  containers."  N.F. 


ARSENIC 

Arsenum 

As  (74.91) 

Arsenium.  Arsenicum.  Fr.  Arsenic.  Ger.  Arsen.  It. 
Arsenico.  Sp.  Arsenico. 

Arsenic  has  been  known  since  ancient  times. 
It  is  sometimes  found  free  in  nature,  but  is  gen- 
erally combined.  Important  ores  include  realgar, 
AS2S2;  orpiment,  AS2S3;  and  mispickel  or  arseni- 
cal pyrites,  FeAsS.  The  element  is  usually  pre- 
pared by  heating  the  last-named  ore  in  the  absence 
of  air,  the  arsenic  subliming.  When  heated  under 
pressure,  arsenic  can  be  melted;  its  melting  point 
at  36  atmospheres  is  814°.  At  atmospheric  pres- 
sure it  sublimes  at  about  450°.  The  element  exists 
in  several  allotropic  modifications,  of  which  the 
steel-gray  form,  having  a  metallic  luster  and  a 
density  of  about  5.7,  is  the  most  important. 

Two  oxides  of  arsenic  are  known.  Arsenous 
oxide  or  anhydride  (white  arsenic)  is  the  trioxide, 
AS2O3,  formed  when  the  metal  is  heated  in  air. 
For  further  information  on  this  substance,  see 
under  Arsenic  Trioxide.  The  higher  oxide  is 
arsenic  oxide  (arsenic  pentoxide) ;  it  is  formed  by 
the  oxidation  of  the  trioxide  suspended  in  con- 
centrated nitric  acid  and  heated.  It  is  a  white, 
amorphous  mass  which  melts  at  a  dull  red  heat. 
It  is  hygroscopic,  absorbing  water  to  form 
H3ASO4,  orthoarsenic  acid.  Chemically,  arsenic 
behaves  as  a  metal  only  toward  the  halide  acids; 
it  does  not  form  salts  with  the  oxygen  acids.  Two 
classes  of  compounds  are  known  in  which  arsenic 
is  acid- forming :  the  arsenites  derived  from  the 
trioxides,  and  arsenates,  derived  from  arsenic 
pentoxide.  In  these  compounds,  arsenic  closely 
resembles  phosphorus. 

Arsenic  added  in  small  amount  (1  in  1000)  to 
lead  increases  its  hardness.  It  is  used  for  this  pur- 
pose in  making  lead  shot.  Large  quantities  of 
arsenic  compounds,  especially  those  of  lead  and 
copper,  are  used  in  plant  sprays  as  insecticides. 

Arsine  is  of  interest  because  of  its  extraor- 
dinary toxic  properties.  Most  metallic  ores  con- 
tain arsenic  as  an  impurity.  On  contact  with  sul- 
furic acid  such  metals  give  off  hydrogen  arsenide, 
H3AS,  or  arsine,  which  is  a  colorless,  inflammable 
gas,  with  a  strong  garlic-like  odor,  approximately 
2.7  times  as  heavy  as  air.  Cases  of  poisoning  have 
been  reported  arising  from  arsine  generated  in 
storage  batteries,  in  smelting  and  other  chemical 
industries  (Spolyar  and  Harger,  Arch.  Ind.  Hyg. 
Occup.  Med.,  1950,  1,  419;  Morse  and  Setterlind, 
ibid.,  2,  148;  Josephson  et  al.,  ibid.,  1951,  4,  43; 
Steel  and  Feltham,  Lancet,  1950,  1,  108).  The 
symptoms  do  not  appear  until  some  hours  after 
exposure  to  the  gas.  They  begin  with  headache, 
followed  by  nausea  and  vomiting  and  chills.  The 
gas  destroys  red  blood  cells,  in  vivo.  Acute  hemo- 
lytic anemia  with  hemoglobinuria  and  jaundice 
develops.  Neuropathy  may  develop.  The  only 
treatment,  outside  of  removal  from  exposure,  is 
that  for  acute  hemolytic  anemia — rest,  inhalation 
of  oxygen,  blood  transfusions,  alkalinization  of 
the  urine. 

The  detection  of  arsenic  in  forensic  procedures 
is  of  great  importance,  several  tests  being  of  espe- 


no 


Arsenic 


Part  I 


rial  usefulness  for  such  purposes.  In  the  Reinsch 
test  arsenic  is  detected  by  deposition,  as  copper 
arsenide,  on  metallic  copper  placed  in  a  hydro- 
chloric acid  solution  of  the  sample  to  be  tested; 
the  identity  of  the  arsenic  compound  is  confirmed 
by  heating  in  an  ignition  tube  with  access  to  air 
whereupon,  if  arsenic  is  present,  a  sublimate  of 
crystals  of  arsenic  trioxide  is  obtained  in  the  cooler 
part  of  the  tube.  In  the  Marsh  test  the  presence 
of  arsenic  is  evidenced  by  treating  the  sample  with 
nascent  hydrogen  (produced  by  the  reaction  of 
zinc  and  acid),  by  which  arsenic  is  reduced  to  the 
gas  arsine;  this,  when  burned,  decomposes  to  form 
arsenic  which  may  be  deposited  on  a  cool  surface 
as  a  brown  to  black  mirror  and  which  is  soluble 
in  sodium  hypochlorite  solution.  The  modified 
Gutzeit  test,  employed  officially  in  testing  for 
arsenic  in  medicinals,  involves  formation  of  arsine 
as  in  the  Marsh  test,  but  its  presence  is  detected 
by  the  formation  of  a  yellow  to  brown  stain  on 
mercuric  bromide  paper.  Bettendorf's  test,  used 
chiefly  in  testing  antimony  compounds  because 
the  latter  element  does  not  interfere  in  the  test, 
depends  on  the  reduction  of  arsenic  to  the  ele- 
mental state  by  stannous  chloride ;  the  arsenic  de- 
posits as  a  black  precipitate. 

For  medicinal  uses  of  arsenic  compounds  see 
under  Arsenic  Trioxide  and  Carbarsone. 

ARSENIC  TRIOXIDE. 

N.F.,  B.P.,  LP. 

Arsenious  Acid,  Arsenious  Oxide,   [Arseni  Trioxidum] 

"Arsenic  Trioxide,  when  dried  at  105°  for  2 
hours,  contains  not  less  than  99.5  per  cent  of 
AS2O3.  Caution. — Arsenic  Trioxide  is  extremely 
poisonous."  N.F.  The  B.P.  requires  not  less  than 
99.8  per  cent  of  AS2O3,  the  calculation  being  re- 
ferred to  the  substance  as  it  is  found.  The  LP. 
requires  not  less  than  99.5  per  cent  of  AS2O3, 
calculated  with  reference  to  the  substance  dried 
at  100°  for  3  hours. 

LP.  Arseni  Trioxydum.  Arsenous  Acid  Anhydride; 
Arsenic  Sesquioxide;  White  Arsenic;  "Arsenic."  Acidum 
Arsenosum;  Acidum  Arsenicosum;  Arsenicum  Album; 
Anhydridum  Arseniosum.  Fr.  Anhydride  arsenieux ;  Acide 
arsenieux;  Arsenic  blanc;  Oxyde  blanc  d'arsenic.  Ger. 
Arsenige  Saure ;  Arsentrioxyd;  Arsenigsaureanhydrid.  It. 
Anidride  arseniosa;  Acido  arsenioso;  Arsenico  bianco.  Sp. 
Anhidrido  arsenioso;  Trioxido  de  Arsenico;  Acido 
arsenioso. 

Arsenic  trioxide  is  found  native  in  octahedral 
crystals,  called  arsenalite,  or  as  monoclinic  crys- 
tals, called  clandetite.  It  is  formed  when  arsenic 
or  arsenical  minerals  are  heated  or  roasted  in  the 
presence  of  air,  and  is  a  by-product  in  a  number 
of  metallurgic  operations,  as  in  the  roasting  of 
cobalt,  copper,  lead,  nickel  and  tin  ores.  The 
arsenic  trioxide  condenses  as  an  impure  dust,  and 
is  purified  by  resublimation. 

Description. — "Arsenic  Trioxide  occurs  as  a 
white,  odorless  powder.  It  is  stable  in  air.  Arsenic 
Trioxide  is  slowly  soluble  in  water.  It  is  slightly 
soluble  in  alcohol  and  in  ether,  and  freely  soluble 
in  glycerin.  It  is  soluble  in  hydrochloric  acid  and 
in  solutions  of  alkali  hydroxides  and  carbonates." 
N.F.  The  B.P.  describes  it  as  a  heavy  white 
powder,  or  irregular  lumps  having  a  vitreous  frac- 
ture, usually  appearing  stratified,  and  containing 
frequently  both  transparent  and  opaque  varieties. 


The  solubility  is  given  as  1  part  in  60  parts  of 
water,  the  rate  of  solution  depending  upon  the 
relative  proportion  of  the  two  varieties  present, 
and  upon  the  degree  of  subdivision. 

Standards  and  Tests. — Identification. — A 
yellow  mixture  is  produced  when  hydrogen  sulfide 
T.S.  is  added  to  a  1  in  100  solution  of  arsenic  tri- 
oxide; addition  of  a  few  drops  of  hydrochloric 
acid  to  the  mixture  precipitates  yellow  arsenic  tri- 
sulfide.  Loss  on  drying. — Not  over  1  per  cent, 
when  dried  at  105°  for  2  hours.  Residue  on  igni- 
tion.— Not  over  0.1  per  cent.  Foreign  substances. 
— 1  Gm.  of  arsenic  trioxide  dissolves  completely 
in  10  ml.  of  ammonia  T.S.,  with  the  aid  of  gentle 
heat,  or  leaves  only  a  very  light  trace  of  white, 
insoluble  material.  N.F. 

The  N.F.  has  no  requirement  concerning  the 
fineness  of  powder.  The  U.S. P.  X  required  that 
when  powdered  arsenic  trioxide  was  administered 
in  solid  form  the  particles  should  not  be  greater 
than  0.0125  mm.  in  diameter.  This  specification 
would  appear  to  be  a  desirable  one,  as  it  has  been 
demonstrated  that  the  absorption  of  arsenic  from 
the  alimentary  tract  is  largely  dependent  on  the 
fineness  of  the  powder  administered. 

Assay. — About  200  mg.  of  arsenic  trioxide. 
previously  dried  at  105°  for  2  hours,  is  dissolved 
in  boiling  water  with  the  aid  of  sodium  hydrox- 
ide T.S.;  the  solution  is  neutralized  with  diluted 
sulfuric  acid,  sodium  bicarbonate  is  added,  and 
the  mixture  is  titrated  with  0.1  A7  iodine,  using 
starch  T.S.  as  indicator.  In  the  assay,  the  arsenic 
is  oxidized  from  the  trivalent  to  the  pentavalent 
state.  Each  ml.  of  0.1  N  iodine  represents  4.946 
mg.  of  AS2O3.  N.F. 

Uses. — In  sufficient  concentration  all  of  the 
official  preparations  of  arsenic  are  violent. irritants 
or  escharotics.  Taken  internally  in  a  dose  of  100 
mg.  or  more  they  are  exceedingly  poisonous  to 
both  man  and  the  lower  animals.  Arsenic,  in 
soluble  forms,  is  absorbed  from  the  mucous  mem- 
branes and  skin  and  from  sites  of  parenteral  ad- 
ministration; it  is  distributed  by  the  blood  to  all 
parts  of  the  body,  being  detectable  in  the  hair  in 
about  two  weeks  and  for  many  months  thereafter. 
It  is  found  in  the  urine  within  a  few  hours  after 
oral  or  parenteral  administration  and  excretion 
continues  for  several  weeks;  because  of  its  slow 
elimination,  cumulative  action  is  an  important 
consideration.  For  details  of  a  recent  study  on 
the  storage  and  metabolism  of  arsenic  in  tissues 
see  Ewing  et  al.  {Texas  Rep.  Biol.  Med.,  1950, 
8,  556;  1951,  9,  27). 

The  local  application  of  arsenic  produces  mild 
irritation  followed,  after  prolonged  or  repeated 
application,  by  necrosis  of  tissue.  Because  rapidly 
proliferating  tissue  appears  to  be  most  sensitive 
to  this  action  of  arsenic  it  has  been  used  in  a 
variety  of  mixtures  ("cancer  paste")  for  the  local 
treatment  of  neoplastic  growths  but  its  lack  of 
penetration  into  the  deeper  portions  of  the  tumor 
makes  it  ineffective  (see  U.S.D.,  21st  ed.,  p.  188). 
Arsenic  is  a  marked  capillary  poison,  causing 
dilatation  and  abnormal  permeability  with  a  re- 
sulting loss  of  protein  and  other  blood  plasma 
constituents  into  the  tissues.  Edema  is  a  common 
manifestation  of  arsenic  poisoning.  The  blood 
pressure  does  not  decrease  until  the  arterioles  are 


Part  I 


Arsenic  Trioxide 


111 


similarly  damaged  or  the  loss  of  blood  volume  be- 
comes significant.  The  myocardium  is  also  de- 
pressed. Hyperemia  of  the  gastrointestinal  tract 
follows  either  oral  or  parenteral  administration 
and  may  promote  the  formation  of  digestive  se- 
cretions and  the  absorption  of  food.  Slightly  larger 
doses,  however,  cause  severe  irritation  of  the 
mucosa  with  the  formation  of  submucosal  blebs 
and  the  loss  of  blood  plasma  into  the  lumen  of 
the  bowel  accompanied  by  increased  peristalsis, 
a  condition  which  results  in  "rice  water"  stools 
which  may  become  bloody.  Vomiting  is  frequent. 
In  addition  to  its  action  on  the  capillaries  of  the 
glomeruli  of  the  kidney,  arsenic  produces  necrosis 
and  degeneration  of  the  tubules.  Oliguria,  albu- 
minuria, hematuria  and  cylindruria  are  observed 
and  the  clinical  features  of  the  nephrotic  stage  of 
glomerular  nephritis  may  develop.  Vasodilatation 
in  the  skin  causes  a  "healthy"  flush  but,  except  in 
minimal  doses,  abnormal  proliferation  of  the  skin 
and  other  epidermal  structures  such  as  the  hair 
and  nails  results.  Peripheral  neuropathy  involv- 
ing both  the  sensory  and  the  motor  elements  is  a 
frequent  result  of  large  doses  of  arsenic  or  pro- 
longed exposure  to  smaller  amounts.  Cell  forma- 
tion in  the  bone  marrow  is  temporarily  stimu- 
lated, then  depressed  to  a  degree  dependent  on  the 
amount  of  arsenic;  this  involves  both  the  red  and 
the  white  blood  cell-forming  elements.  In  toxic 
doses  arsenic  increases  the  excretion  of  nitrogen 
due  to  its  destructive  action  on  the  tissues  of 
many  organs  of  the  body.  For  many  years  small 
doses  of  arsenic  were  employed  as  a  tonic  in  con- 
valescent, neurasthenic,  and  malnourished  pa- 
tients. Although  a  decreased  excretion  of  nitrogen 
and  of  carbon  dioxide  has  been  reported,  the 
cumulative  action  of  arsenic  has  made  it  clinically 
impractical  to  avoid  toxic  effects  and  this  use  of 
arsenic  is  no  longer  popular.  Early  toxic  effects 
may  even  simulate  clinical  improvement  through 
a  flushed  skin,  minimal  edema,  and  possibly  im- 
proved absorption  induced  by  hyperemia  of  the 
intestinal  tract. 

The  apparent  tolerance  to  arsenic  developed  by 
the  mountaineers  of  Styria  and  the  Tyrol  who  are 
able  to  consume  large  quantities  is  explicable  on 
the  basis  of  the  insolubility  and  poor  absorbability 
of  the  form  ingested  (/.  Pharmacol.,  1922,  20, 
181);  no  tolerance  has  been  observed  following 
parenteral  administration  of  arsenic  compounds. 

Although  arsenic  is  a  protoplasmic  poison  it 
does  not  actively  precipitate  protein  and  in  con- 
centrations and  forms  which  are  not  caustic  its 
action  is  slow.  The  theory  that  arsenic  interferes 
with  essential  protoplasmic  oxidation  and  reduc- 
tion processes  has  long  been  held.  Voegtlin  and 
his  associates  {Pub.  Health  Rep.,  1923,  38,  1882; 
/.  Pharmacol.,  1930,  39,  347)  produced  evidence 
that  arsenic  combines  with  the  sulfhydryl  ( — SH) 
groups  in  cells  to  prevent  normal  oxidative  proc- 
esses both  in  vitro  and  in  vivo.  They  found  that 
the  administration  of  substances  with  free  sulfhy- 
dryl groups  had  prophylactic  and  therapeutic 
value  against  the  action  of  arsenic  on  mammals 
and  on  protozoa.  Eagle  and  his  associates  (/.  Phar- 
macol, 1938,  64,  164  and  1939,  66,  10  and  436; 
Am.  J.  Syph.  Gonor.  Ven.  Dis.,  1939,  23,  310) 
and  Kolmer  and  his  colleagues   (Am.  J.  Syph. 


Gonor.  Ven.  Dis.,  1940,  24,  201)  have  also  pre- 
sented information  on  the  mechanism  of  the  action 
of  arsenic.  Eagle  et  al.  (Fed.  Proc,  1946,  5,  175) 
and  others  (Science,  1945,  102,  601)  have  re- 
ported that  the  dithiol  compound,  dimercaprol 
(q.v.),  is  far  superior  to  the  monothiol  com- 
pounds such  as  glutathione,  methionine  (Peters 
et  al.,  Quart.  J.  Med.,  1945,  14,  35),  etc.  in  the 
prevention  and  treatment  of  arsenical  poisoning 
in  man,  animals,  and  protozoa.  Arsenic  inhibits 
the  action  of  cellular  enzymes  (Maver  and 
Voegtlin,  Am.  J.  Cancer,  1937,  29,  333)  and  pre- 
vents mitosis  and  other  nuclear  functions.  The 
hazard  of  epithelioma  of  the  skin  in  occupations 
with  exposure  to  arsenic  is  presented  by  Hueper 
(Occup.  Med.,  1948,  5,  157)  and  Hill  and  Faning 
(Brit.  J.  Ind.  Med.,  1948,  5,  1). 

In  dentistry,  equal  parts  of  arsenic  trioxide  and 
cocaine  hydrochloride  made  into  a  stiff  paste  with 
creosote  is  used  in  root  canals  to  destroy  ("kill") 
the  nerve.  Utilizing  the  radioactive  isotope,  As76, 
Gotte  et  al.  (Ztschr.  Naturforsch.,  1951,  6b,  274) 
showed  that  the  arsenic  diffused  into  the  dentin 
to  a  considerable  extent,  where  it  may  cause  latent 
degenerative  changes. 

Although  the  inorganic  forms  of  arsenic  are 
highly  toxic  to  many  protozoa  they  are  less  suc- 
cessful in  the  treatment  of  parasitic  infections 
than  the  organic  forms,  because  the  latter  can  be 
given  in  so  much  larger  doses  without  danger  to 
the  host  (see  Carbarsone).  To  what  action  arsenic 
owes  its  value  in  pulmonary  diseases  is  unknown 
but  there  has  been  a  clinical  impression  that  in 
chronic  bronchitis,  especially  of  the  aged,  and  in 
asthma,  it  is  beneficial.  With  the  advent  of  liver 
therapy,  arsenic  was  abandoned  in  pernicious 
anemia. 

When  preparations  of  arsenic  are  given  for  their 
tonic  effect  alone,  they  should  be  used  in  doses  so 
small  as  not  to  cause  any  general  symptoms  (see 
also  Potassium  Arsenite  Solution).  Mixtures  of 
arsenic  with  nux  vomica,  quinine  and  other  "bit- 
ters" are  less  popular  than  formerly.  To  avoid 
gastrointestinal  irritation,  pain  and  diarrhea  as 
much  as  possible,  the  remedy  should  be  given 
after  meals.  S 

Toxicology. — The  specific  symptoms  of  ar- 
senicalism  are  a  general  disposition  to  edema, 
especially  of  the  face  and  eyelids,  a  feeling  of 
stiffness  in  these  parts,  itching  of  the  skin,  tender- 
ness of  the  mouth,  loss  of  appetite,  and  uneasi- 
ness and  sickness  of  the  stomach,  usually  with 
diarrhea.  The  symptoms  of  chronic  arsenic  poison- 
ing are  so  protean  as  to  defy  detailed  description ; 
most  of  them  fall  into  3  groups.  First,  those  due 
to  irritation  of  the  gastrointestinal  tract,  nausea 
and  diarrhea;  or,  when  the  arsenic  has  been  in- 
haled, symptoms  of  laryngitis  and  bronchitis. 
Second,  when  used  continuously  over  long  periods 
of  time,  even  in  doses  too  small  to  cause  the  cus- 
tomary symptoms  of  arsenicalism,  the  drug  may 
give  rise  to  alterations  in  the  skin.  The  most  im- 
portant of  these  are  peculiar  dryness  and  a  tend- 
ency to  the  overgrowth  of  keratin  as  shown  by 
the  formation  of  warts,  ridges  on  the  finger  nails 
or  coarseness  of  the  hair.  In  the  diagnosis  of  sus- 
picious cases  of  arsenic  poisoning,  chemical  ex- 
amination of  the  hair  or  finger  nails  for  arsenic 


112 


Arsenic  Trioxide 


Part  I 


is  valuable  (Althausen  and  Gunther,  J.A.M.A., 
1929,  92,  2002;  Hamori,  Deutsche  med.  Wchn- 
schr.,  1941,  67,  628).  In  some  instances  the  in- 
ternal use  of  arsenic  causes  a  rash  not  unlike  that 
of  measles  attended,  as  in  that  affection,  with 
catarrhal  symptoms.  Sometimes  salivation  is  pro- 
duced, and  occasionally  the  hair  and  nails  fall  off. 
Third,  the  group  of  cases  in  which  peripheral 
neuritis  is  the  outstanding  manifestation.  This 
neuropathy  may  involve  either  motor  or  sensory 
elements  with  paralysis,  paresthesia  or  pain.  Im- 
paired vision  has  resulted.  Any  of  these  symptoms 
call  for  the  discontinuance  of  arsenic  therapy. 

Arsenic  is  still  one  of  the  most  commonly  used 
poisons  for  criminal  purposes.  Arsenic  compounds 
are  used  as  insecticides  and  rodenticides  and  acci- 
dental human  poisoning  occurs.  The  symptoms  of 
acute  poisoning,  which  generally  do  not  appear 
for  a  period  of  from  one-half  to  one  hour  after 
the  ingestion  of  the  poison,  are  somewhat  varied 
in  different  cases.  The  most  frequent  are;  pain  in 
the  epigastrium;  vomiting,  the  vomitus  being 
occasionally  bloody,  more  commonly  not;  profuse 
serous  purging;  great  thirst;  rapid,  weak  pulse; 
prostration  and  restlessness,  sometimes  with  de- 
lirium and  convulsions.  Any  or  all  of  these  symp- 
toms, however,  may  be  lacking,  death  occasionally 
taking  place  with  no  prodromal  symptoms  except 
heart  failure  or  stupor.  At  post-mortem  examina- 
tion there  will  be  found  evidence  of  inflammation 
of  the  alimentary  canal  and  of  the  kidney  and  fre- 
quently fatty  degeneration  in  various  of  the  in- 
ternal organs.  In  the  series  of  cases  of  arsenic 
poisoning  reported  by  Lawson  {J. A.M. A.,  1925, 
85,  24)  enlargement  of  the  liver  was  observed 
in  more  than  half  of  the  cases  and  enlargement 
of  the  spleen  in  about  one-quarter.  Death  usually 
occurs  in  the  fatal  cases  within  48  hours  (few 
hours  to  several  weeks). 

The  diagnosis  of  acute  arsenical  poisoning  is 
sometimes  impossible  without  chemical  examina- 
tion. For  the  methods  of  detecting  arsenic  in  the 
human  body,  see  U.S.D.,  19th  ed.,  p.  202  and 
Morris  and  Calvery,  Ind.  Eng.  Chem.,  Anal.  Ed., 
1937,  9,  447.  It  should  be  remembered  that  even 
after  the  post-mortem  injection  of  arsenic,  as  in 
the  use  of  some  embalming  fluids,  the  poison  may 
be  diffused  throughout  the  entire  body. 

In  the  treatment  of  poisoning  by  arsenic,  it  is 
of  the  utmost  importance  to  prevent  the  absorp- 
tion of  the  drug,  because  after  the  poison  has  once 
entered  the  system,  it  is  difficult  to  mollify  its 
baneful  effects.  The  most  important  method  of 
preventing  absorption  is  the  mechanical  evacua- 
tion of  the  stomach — unless  nature  has  already 
done  so  by  vomiting — either  by  use  of  the  stomach 
tube  with  large  amounts  of  warm  water  or  milk, 
or  by  means  of  a  promptly  acting  emetic  such  as 
2  Gm.  (approximately  30  grains)  of  zinc  sulfate 
in  water.  It  is  to  be  remembered  that  the  poison 
may  remain  in  the  stomach  for  long  periods,  espe- 
cially if  it  has  been  taken  in  solid  form,  and 
cleansing  of  the  stomach  is  advisable  even  if  the 
patient  is  not  seen  immediately  after  the  ingestion. 
Prior  to  evacuation  of  the  stomach,  the  inges- 
tion of  a  precipitant  or  adsorbent  to  decrease  the 
amount  of  dissolved  arsenic  available  for  absorp- 
tion seems  rational.  Formerly,  a  freshly  precipi- 


tated ferric  hydroxide  suspension  {Magma  Ferri 
Hydroxidi,  U.S. P.  XI)  was  advocated  (see  U.S.D., 
24th  ed.,  p.  105),  this  being  prepared  by  adding 
a  solution  of  ferric  sulfate  to  a  suspension  of 
magnesium  oxide  in  water  or  to  magnesia  magma. 
A  quick  substitute  may  be  prepared  by  adding 
any  alkaline  hydroxide  solution  to  the  solution  of 
any  available  soluble  ferric  salt.  Evacuation  of 
the  intestines  by  a  saline  purgative  such  as  mag- 
nesium sulfate  should  follow  removal  of  the 
gastric  contents.  Loss  of  fluid  and  electrolytes 
should  be  corrected  by  intravenous  injection  of 
isotonic  sodium  chloride  solution. 

As  soon  as  the  diagnosis  of  arsenic  poisoning 
has  been  made,  whether  it  is  in  an  early  or  a  late 
stage,  Dimercaprol  Injection  (q.v.)  should  be 
given  intramuscularly  in  a  dose  of  2.5  to  3  mg. 
of  dimercaprol  per  kilo  of  body  weight  and  re- 
peated every  4  hours  for  3  or  4  doses;  if  neces- 
sary, single  daily  doses  should  be  continued  for 
several  days  (Bull.  U.  S.  Army  M.  Dept.,  1945, 
Xo.  88,  13).  In  acute  and  severe  cases  the  inter- 
val between  the  first  and  second  doses  should  be 
shortened  to  2  hours.  Eagle  reported  the  urinary 
excretion  of  arsenic  to  be  increased  as  much  as 
100  times  during  1  to  2  hours  after  each  injection, 
with  an  incidence  of  only  1  per  cent  of  untoward 
reactions.  The  reactions  usually  occur  within  15 
to  30  minutes  after  the  injection  and  consist  of 
sensations  of  constriction  in  the  throat,  oppression 
in  the  chest,  burning  of  the  lips,  lacrimation  and 
congestion  of  the  conjunctiva,  local  tenderness, 
restlessness  and  nervousness,  sweating  of  the 
hands,  mild  nausea  and  vomiting,  headache  and  a 
transient  rise  in  blood  pressure.  Since  the  intro- 
duction of  dimercaprol  the  use  of  sodium  thio- 
sulfate  routinely  in  the  treatment  of  arsenical 
poisoning  has  been  abandoned.  Evidence  for  its 
value  was  never  clear  (J.A.M.A.,  1942,  120,  124). 
Although  Ayres  and  Anderson  (J.A.M.A.,  1938, 
110,  886)  reported  that  sodium  thiosulfate  in- 
creased the  urinary  excretion  of  arsenic,  Muir, 
Stenhouse  and  Becker  (Arch.  Dermat.  Syph., 
1940,  41,  308)  and  other  observers  found  no  such 
action. 

The  subsequent  treatment  consists  in  the  ad- 
ministration of  mucilaginous  drinks,  and  the  treat- 
ment of  symptoms  as  they  arise.  An  adequate 
intake  of  protein,  carbohydrate  and  vitamins, 
orally  or  parenterally,  is  important.  Conva- 
lescence is  generally  long  and  distressing;  usually 
dyspeptic  symptoms  mark  the  presence  of  gastro- 
intestinal inflammation  or  even  ulceration,  while 
not  rarely  violent  neuralgic  pains,  with  loss  of 
power,  wasting  of  the  muscle,  and  other  trophic 
changes,  show  that  a  peripheral  neuritis  has  been 
produced. 

Chronic  arsenical  poisoning  is  a  not  infrequent 
— but  often  unrecognized — result  of  the  continued 
absorption  of  small  amounts  of  the  element 
through  either  the  alimentary  or  the  respiratory 
tract.  It  has  occurred  from  the  inhalation  of  the 
dust  of  arsenical  pigments,  from  the  ingestion  of 
contaminated  foods  and  from  the  prolonged  use 
of  medicinal  preparations.  The  arsenical  dyes  are 
not  used  today  for  coloring  foods,  but  vegetables 
and  fruit  are  occasionally  injurious  from  the  resi- 
due of  agricultural  insecticides.  A  serious  epi- 


Part  I 


Asafetida 


113 


demic  in  Manchester,  England,  in  1900  was  traced 
to  contaminated  sulfuric  acid  used  in  making  glu- 
cose. The  increasing  use  of  arsenic  sprays,  espe- 
cially lead  arsenate,  in  agriculture  constitutes  a 
menace  to  public  health  (Calvery,  J. A.M. A.,  1938, 
111,  1722).  Some  of  these  foods  enter  our  mar- 
kets today  containing  enough  arsenic  to  be  po- 
tentially dangerous. 

Dose,  of  arsenic  trioxide,  1.5  to  3  mg.  (ap- 
proximately y±o  to  V20  grain) . 

Storage. — Preserve  "in  well-closed  containers." 
N.F. 

Off.  Prep.— Arsenic  Trioxide  Tablets,  N.F.; 
Potassium  Arsenite  Solution,  N.F.,  B.P. 

ARSENIC   TRIOXIDE  TABLETS.  N.F. 

Arsenous  Acid  Tablets,  [Tabellae  Arseni  Trioxidi] 

"Arsenic  Trioxide  Tablets  contain  not  less  than 
92.5  per  cent  and  not  more  than  107.5  per  cent  of 
the  labeled  amount  of  AS2O3."  N.F. 

Assay. — A  representative  sample  of  powdered 
tablets,  equivalent  to  about  60  mg.  of  arsenic  tri- 
oxide, is  boiled  with  water  and  then  hydrochloric 
acid  and  chloroform  are  added  and  the  mixture 
allowed  to  stand  two  hours,  with  occasional  agi- 
tation. The  mixture  is  then  titrated  with  0.02  M 
potassium  iodate  until  the  purple  color  which  de- 
velops in  the  chloroform  layer  during  the  first 
part  of  the  titration  is  discharged.  In  the  reaction 
with  iodate  the  arsenic  is  oxidized  to  the  pentava- 
lent  state  while  the  iodate  is  reduced  to  iodine, 
which  gives  to  chloroform  the  purple  color; 
further  addition  of  iodate  oxidizes  the  iodine  to 
iodine  monochloride,  IC1,  in  which  iodine  has  a 
valence  of  +1.  One  mole  of  arsenic  trioxide  is 
equivalent  to  one  mole  of  potassium  iodate;  ac- 
cordingly, 1  ml.  of  0.02  M  potassium  iodate  repre- 
sents 3.956  mg.  of  AS2O3.  N.F. 

Usual  Size. — 2  mg.  (approximately  Vao  grain). 

ASAFETIDA.     N.F. 

Gum  Asafetida,  [Asafoetida] 

"Asafetida  is  the  oleo-gum-resin  obtained  by 
incising  the  living  rhizome  and  roots  of  Ferula 
Assa-fcetida  Linne,  Ferula  rubricaulis  Boissier, 
and  of  Ferula  jcetida  (Bunge)  Regel,  and  prob- 
ably of  other  species  of  Ferula  (Fam.  Umbel- 
lifer  cb.)"  N.F. 

Gum  Asafetida;  Devil's  Dung.  Asa  Foetida;  Gum- 
miresina  Asafoetida.  Fr.  Asa  fcetida.  Ger.  Asant ;  Teufels- 
dreck.  It.  Assa  fetida.  Sp.  Asafetida.  Pers.  Ungoozeh. 
Arab.  Hilteet.  Ind.  Hing.  Afgh.  Angusakema. 

Asafetida  appears  to  have  been  introduced  into 
European  medicine  by  the  Arabian  physicians.  It 
was  in  use  in  continental  Europe  during  the  Mid- 
dle Ages.  It  has  long  been  recognized  in  the  U.S. P. 
but  was  deleted  from  the  twelfth  revision  and 
admitted  to  the  N.F.  VII.  The  plants  from  which 
it  is  obtained  are  natives  of  western  Afghanistan 
and  eastern  Persia. 

Ferula  Assa-fcetida  was  first  described  from 
actual  observation  by  H.  Falconer,  who  found 
it  near  Kashmir,  and  it  has  long  been  successfully 
cultivated  in  the  Edinburgh  Botanical  Gardens. 
It  is  distinguished  from  allied  plants  by  the  greater 
height  of  the  stem  (6  to  10  feet),  and  by  the 
numerous  stem  leaves  furnished  with  broad  sheath- 


ing petioles.  The  flowers  are  pale  yellow,  and  the 
oval  fruit  thin,  flat,  foliaceous,  and  reddish  brown, 
with  pronounced  vittae.  It  yields  a  milky  juice 
having  a  powerful  odor  of  asafetida. 

Ferula  fcetida  is  a  coarse  umbelliferous  plant, 
growing  from  5  to  7  feet  high,  with  a  large  fleshy 
root,  the  crown  of  which  is  covered  with  coarse 
bristly  fibers,  and  gives  origin  to  large  bipinnate 
radical  leaves  and  a  nearly  naked  stem  which  has 
only  a  few  bipinnate  leaves  and  ends  at  the  top 
in  very  numerous  umbels.  This  plant  was  first  dis- 
covered in  the  sandy  desert  near  the  sea  of  Aral, 
by  Lehmann,  in  1844.  Bunge  found  it  in  Persia 
about  twenty  years  later.  It  would  seem  to  be 
native  all  through  Afghanistan. 

Ferula  rubricaulis  Boissier  is  mentioned  as  a 
source  of  galbanum  in  the  Pharmacographia,  2nd 
ed.,  and  in  Bentley  and  Trimen's  Medicinal  Plants, 
but  Holmes,  studying  Kotscky's  specimen  in  the 
British  Museum,  classifies  it  with  the  asafetida 
plants  partly  because  its  fruit  possesses  an  allia- 
ceous taste  which  is  wanting  in  the  fruit  of  the 
galbanum  and  partly  because  Boissier  placed  this 
species  in  his  Sect.  Scorodosma  along  with  Ferula 
Assafcetida  and  F.  alliacea,  both  of  which  are  con- 
sidered as  sources  of  asafetida.  F.  rubricaulis  is 
claimed  by  Holmes  to  yield  some  of  the  white 
asafetida  of  commerce.  Its  mericarp  fruits  are 
said  to  be  glabrous  with  broad  thick  wings,  no 
vittae,  the  three,  primary,  dorsal  ridges  being  in- 
conspicuous; there  are  12  to  14  vittae  on  the 
dorsal  and  8  to  10  on  the  ventral  side,  the  cuticle 
on  the  dorsal  surface  is  especially  thick;  the  sub- 
epidermal tissue  is  many  layers  thick;  the  cells 
between  the  epidermis  and  the  vittae  are  thin 
walled,  while  those  on  the  opposite  side  of  the 
vittae  are  tracheid-like  in  form.  The  plant  is  a 
native  of  Persia. 

On  the  basis  of  the  study  of  fruits  found  in  a 
mixed  sample  of  gum  resin  of  asafetida,  J.  Small 
concluded  that  Ferula  rubricaulis  yields  some  of 
the  "white  asafetida"  and  F.  fcetida,  the  "red 
asafetida."  Both  of  these  varieties  occur  in  com- 
merce. Both  contain  tears  which  when  fresh  are 
milky  white  or  yellowish  internally.  In  the  case 
of  the  red  variety,  the  freshly  exposed  surface  of 
the  fractured  tear  gradually  changes  in  color  to 
pink,  red,  and  finally  reddish-brown,  whereas  in 
that  of  the  white  variety  it  remains  almost  white. 

It  is  possible  that  asafetida  is  obtained  from 
other  species  of  Ferula,  but  the  bulk  of  the  drug 
probably  comes  from  the  plants  named  in  the 
official  definition.  Among  the  other  plants  yielding 
asafetida  is  Ferula  Narthex  Boiss.  While  this  is 
disputed  by  Aitchison  yet  it  appears  that  it  is 
the  source  of  the  gum-resin  obtained  from  certain 
portions  of  Afghanistan.  Tschirch  describes  this 
plant  with  illustrations  in  Schweiz  Wchnschr. 
Pharm.,  1910,  p.  289.  Holmes's  discussion  of  the 
asafetida  plants  {Pharm.  J.,  ser.  iii,  19,  1888- 
1889)  still  remains  one  of  our  chief  sources  of 
information  on  the  subject.  (See  also  article  on 
the  sources  of  the  fetid  gum-resins  by  James 
Small,  Pharm.  J.,  1913,  90,  287.) 

The  asafetida  plants  are  indigenous  to  western 
Afghanistan  and  eastern  Persia.  The  great  cab- 
bage-like heads  of  the  asafetida  plant,  represent- 
ing the  primary  stage  of  the  flower  heads  covered 


114 


Asafetida 


Part  I 


over  by  the  stipules  of  its  leaves,  are  eaten  raw 
by  the  natives  as  a  sort  of  green.  Collection  of 
the  drug  begins  in  mid-April  and  proceeds  until 
late  in  July.  The  root-stock  is  first  laid  bare  by 
sawing  off  the  head,  those  plants  only  which  have 
not  reached  their  flower-bearing  stage  being 
selected.  A  slice  is  then  taken  from  the  top  of 
the  root-stock,  which  is  immediately  covered  with 
twigs  and  clay,  forming  a  sort  of  dome,  with  an 
opening  toward  the  north,  so  that  the  sun  cannot 
get  at  the  exposed  root.  About  five  or  six  weeks 
later,  a  thick,  gummy,  not  milky,  reddish  sub- 
stance found  upon  the  exposed  surface  of  the  rhi- 
zome in  more  or  less  irregular  lumps  is  scraped 
off  with  a  piece  of  iron  hoop  or  removed  with  a 
slice  of  the  rhizome  and  at  once  placed  in  a 
leather  bag.  The  product  of  many  plants  is  mixed 
and  permitted  to  harden  in  the  sun.  The  process 
is  continued  for  a  second  and  third  time,  the  root- 
stock  being  cut  lower  on  each  occasion. 

Most  of  the  drug  is' normally  gathered  in  eastern 
Persia  and  western  Afghanistan.  It  is  brought  to 
Herat  and  Kandahar,  whence  it  enters  com- 
merce, being  exported  from  Bunder  Abbas  and 
other  Persian  Gulf  ports  to  Bombay  and  thence 
to  Europe  and  the  United  States,  usually  arriving 
in  tin-fined  cases.  In  1952  importations  of  the 
drug,  from  Iran,  amounted  to  83,175  pounds  and 
from  Switzerland,  11,200  pounds. 

Description. — "Asafetida  occurs  as  a  soft 
mass  sometimes  almost  semi-liquid,  or  as  irregu- 
lar, more  or  less  pliable  masses  composed  of 
agglutinated  tears  imbedded  in  a  weak  brown  to 
moderate  yellowish  brown  matrix,  or  as  loose 
ovoid  tears,  from  0.5  to  4  cm.  in  diameter,  with  a 
few  vegetable  fragments.  It  becomes  hard  and 
occasionally  brittle  on  drying.  The  surface  of  the 
freshly  fractured  tears  is  white  to  moderate  yel- 
lowish brown,  changing  gradually  on  exposure 
to  air  or  light  to  a  strong  pink  and  finally  to  a 
moderate  yellowish  brown.  When  moistened  with 
water  the  tears  become  moderate  orange  to  weak 
yellow.  The  odor  is  persistent  and  alliaceous,  and 
the  taste  is  bitter,  alliaceous,  and  acrid."  7V..F. 

Standards  and  Tests. — Identification. — (1) 
A  yellowish  orange  emulsion,  turning  to  greenish- 
yellow  on  addition  of  alkalies,  is  formed  when 
asafetida  is  triturated  with  water.  (2)  A  reddish 
brown  solution  results  when  a  fragment  of  asa- 
fetida is  heated  with  sulfuric  acid;  on  diluting 
this  solution  with  a  large  volume  of  water,  filter- 
ing, and  alkalinizing  the  filtrate,  a  purplish  blue 
fluorescence  is  produced.  (3)  A  pink  color  is  pro- 
duced on  adding  a  few  drops  each  of  phloro- 
glucinol  T.S.  and  hydrochloric  acid  to  10  ml.  of 
the  alcoholic  extract  obtained  in  the  assay.  Most 
foreign  resins. — A  yellowish  brown  color  produced 
on  adding  a  few  drops  of  ferric  chloride  T.S.  to  5 
ml.  of  the  alcoholic  extract  obtained  in  the  assay 
indicates  absence  of  most  foreign  resins.  Gal- 
banum. — A  bluish  green  color,  fading  on  stand- 
ing, obtained  when  enough  hydrochloric  acid  to 
produce  a  faint  turbidity  is  added  to  10  ml.  of 
alcoholic  extract  from  the  assay  indicates  absence 
of  galbanum.  Ammoniac. — No  momentary  yel- 
lowish orange  to  red  color  develops  on  adding  5 
ml.  of  sodium  hypobromite  T.S.  to  2  ml.  of  a  1  in 
"24  aqueous  emulsion  of  asafetida  diluted  with  5 


ml.  of  water.  Rosin. — No  green  color  is  formed 
in  the  benzin  layer  on  adding  10  ml.  of  a  fresh  1 
in  200  solution  of  copper  acetate  to  the  filtrate 
from  a  1  in  10  purified  petroleum  benzin  extract 
of  asafetida.  Acid-insoluble  ash. — Not  over  15 
per  cent.  Alcohol-soluble  extractive. — A  sample 
of  2  Gm.  of  asafetida  is  extracted  with  alcohol  in 
a  Soxhlet  or  other  extractor;  the  insoluble  residue 
is  dried  at  105°  for  2  hours  and  weighed.  A  cor- 
rection is  applied  for  the  amount  of  moisture  in 
the  drug,  as  determined  by  the  toluene  distillation 
method,  and  the  content  of  alcohol-soluble  extrac- 
tive calculated.  Asafetida  yields  not  less  than  50 
per  cent  of  such  extractive.  N.F. 

Constituents. — The  odor  of  asafetida,  and 
probably  also  its  therapeutic  virtues,  depend 
chiefly  upon  its  volatile  oil.  When  freshly  distilled 
it  is  a  colorless  liquid  but  it  yellows  on  aging;  it 
has  an  offensive  odor  and  a  taste  which  is  at  first 
flat  but  afterward  bitter  and  acrid.  According  to 
Mannich  and  Fresenius  {Arch.  Pharm.,  1936,  274, 
461),  the  main  fraction  of  this  oil  is  a  mercaptan 
of  the  formula  C7H14S2.  Baumann  (Quart.  J.  P., 
1929,  2,  621)  found  in  a  sample  of  asafetida  69 
per  cent  of  an  acetone-soluble  resin  fraction  and 
31  per  cent  of  gum  and  impurities.  Of  the  resin 
fraction,  50.1  per  cent  (calculated  to  the  original 
material)  consisted  of  resin  and  ethereal  oil.  1  per 
cent  of  ether-insoluble  matter  (apparently  free 
resinol),  16.57  per  cent  of  asaresinol  ferulic  acid 
ester  and  1.33  per  cent  of  free  ferulic  acid.  The 
ester,  which  is  very  labile,  is  responsible  for  the 
change  of  color  of  asafetida  on  standing.  The 
resinol  is  apparently  a  phenol  and  not  coniferyl 
alcohol,  as  has  been  stated.  Vanillin  does  not  occur 
in  the  freshly  gathered  drug  but  is  formed  later 
by  oxidation  of  the  ferulic  acid.  On  distillation  of 
the  resin  in  vacuo,  umbelliferone  was  produced. 
Clevenger  gives  certain  chemical  and  physical 
data  on  asafetida  and  its  volatile  oil,  based  upon 
examination  of  41  lots  of  the  drug  offered  for 
entry  at  the  Port  of  New  York  (/.  A.  Ph.  A., 
1932,  21,  668).  The  content  of  alcohol-soluble 
extractive  varied  from  54.5  to  74.7  per  cent;  that 
of  volatile  oil  ranged  between  7.5  and  12  ml.  per 
100  grams  of  asafetida. 

Impurities  and  Adulterations. — Asafetida 
is  often  purposely  adulterated;  it  frequently 
comes  of  inferior  quality,  and  mixed  with  various 
impurities,  such  as  sand,  stones,  galbanum,  am- 
moniac, gums,  gypsum,  vegetable  tissues,  or  a 
rose-colored  marble.  It  is  generally  conceded  to 
be  the  worst  adulterated  drug  upon  the  market. 
The  gum-resin  imported  from  the  Persian  Gulf 
and  Bombay  is  largely  adulterated  with  sand  and 
other  gum-resins.  In  recent  years,  however,  the 
quality  of  the  available  asafetida  has  materially 
improved. 

Asafetida  is  sometimes  kept  in  a  powdered 
state,  but  this  is  objectionable,  as  the  drug  loses 
volatile  oil,  and  is  more  liable  to  adulteration. 
Powdered  asafetida  is  best  prepared  by  drying  the 
crude  drug  over  freshly  burnt  lime  and  then 
comminuting  it  at  a  low  temperature. 

For  methods  which  have  been  proposed  for  the 
detection  of  adulteration  in  asafetida,  see  U.S.D., 
22nd  ed.,  p.  198. 

Uses. — Asafetida  is  seldom  prescribed  in  the 


Part  I 


Ascorbic  Acid 


115 


United  States.  It  appears  to  have  been  used  in 
the  East  from  the  earliest  times.  Its  therapeutic 
action  probably  arose  from  the  psychic  effect  of 
its  disagreeable  odor  and  taste.  In  small  amounts 
it  gives  the  distinctive  aroma  to  the  type  of  sauce 
known  as  "Worcestershire."  It  is  absorbed  from 
the  intestinal  tract  but  there  is  no  evidence  that 
it  has  any  distinct  action.  Pidoux  took  half  an 
ounce  at  one  dose  without  effects  other  than  local 
action. 

Asafetida  has  been  employed  as  a  carminative 
in  the  treatment  of  flatulent  colic.  In  colic,  espe- 
cially in  infants,  it  is  often  administered  per 
rectum,  either  as  the  emulsion  or  as  a  suppository. 
The  emulsion  is  prepared  by  triturating  4  Gm.  of 
asafetida  with  100  ml.  of  distilled  water  until  a 
uniform  mixture  results,  after  which  it  is  strained; 
15  to  30  ml.  of  this  emulsion  in  500  ml.  of  warm 
water  may  be  given  as  an  enema.  Such  an  enema 
has  been  used  for  abdominal  distention  in  pneu- 
monia and  in  postoperative  cases;  it  is  less  irritant 
than  the  milk  and  molasses  or  the  turpentine 
enema.  Generally  such  enemas  should  not  be  given 
during  the  first  3  days  after  abdominal  surgery, 
and  the  enema  can  should  not  be  placed  higher 
than  25  to  50  cm.  above  the  level  of  the  patient. 

Following  absorption,  the  volatile  oil  of  asa- 
fetida is  eliminated  through  the  lungs,  for  which 
reason  the  drug  has  been  used  as  a  stimulating 
expectorant  in  bronchitis,  whooping  cough,  and 
asthma. 

Because  of  its  disagreeable  taste  asafetida  is 
preferably  administered  as  a  pill  or  coated  tablet. 

Dose,  0.3  to  1  Gm.  (approximately  5  to  15 
grains) . 


ASCORBIC  ACID.     U.S.P.,  B.P.,  LP. 

Vitamin  C,  [Acidum  Ascorbicum] 


ASAFETIDA  PILLS. 

[Pilulae  Asafcetidae] 


N.F. 


Prepare  100  pills,  according  to  the  General  Di- 
rections (see  under  Pills),  from  20  Gm.  of  asa- 
fetida, and  6  Gm.  of  hard  soap,  in  fine  powder, 
using  water  as  the  excipient.  Coat  the  pills,  pref- 
erably with  gelatin,  or  dispense  the  mass  in  gela- 
tin capsules. 

These  pills  are  a  convenient  form  for  admin- 
istering asafetida,  the  unpleasant  odor  and  taste  of 
which  render  it  very  offensive,  particularly  when 
in  liquid  dispersion. 

Dose,  one  to  three  pills. 

ASAFETIDA  TINCTURE.     N.F. 

[Tinctura  Asafcetidae] 

Tinctura  Asa;  Foetidae.  Fr.  Teinture  d'asa  foetida.  Ger. 
Asanttinktur.  It.  Tintura  di  assa  fetida.  Sp.  Tintirra  de 
asafetida. 

Prepare  the  tincture,  by  Process  M  (see  under 
Tinctures),  from  200  Gm.  of  comminuted  asa- 
fetida, using  as  the  menstruum  sufficient  alcohol 
to  make  1000  ml.  of  tincture.  N.F. 

Alcohol  Content. — From  78  to  85  per  cent, 
by  volume,  of  C2H5OH.  N.F. 

Dose,  1  to  4  ml.  (approximately  15  to  60 
minims). 

Storage. — Preserve  "in  tight,  light-resistant 
containers  and  avoid  exposure  to  direct  sunlight 
or  to  excessive  heat."  N.F. 


"Ascorbic  Acid,  dried  in  a  vacuum  desiccator 
over  sulfuric  acid  for  3  hours,  contains  not  less 
than  99  per  cent  of  CeHsOc."  U.S.P.  The  B.P. 
defines  ascorbic  acid  as  the  enolic  form  of  3-keto- 
L-gulofuranolactone;  not  less  than  98  per  cent  of 
CeHsOe  is  required.  The  LP.  requires  not  less 
than  98.0  per  cent  of  CeHsOe,  calculated  with 
reference  to  the  substance  dried  over  sulfuric  acid 
for  24  hours. 

Cevitamic  Acid;  Anti-scorbutic  Vitamin.  Ascorbin  (.Lake- 
side); Cantaxin  (Winthrop);  Cebione  (Merck) ;  Cevalin 
(Lilly) ;  Cevatine  (Premo) ;  Cevimin  (Irwin,  Neisler) ; 
Ciamin  (Massengill)  ;  Vitacee  (Endo).  Sp.  Acido  Ascorbico. 

Scurvy  has  been  for  many  centuries  one  of  the 
great  human  plagues.  It  is  said  that  in  the  17th 
century  more  seamen  died  of  scurvy  than  all  other 
causes  combined — and  it  has  also  been  known  for 
centuries  that  the  disease  was  the  result  of  dietetic 
deficiencies  and  could  be  cured  with  fresh  green 
foods,  lemon  juice,  and  various  other  substances. 

In  1932,  Waugh  and  King  separated  from 
lemon  juice  a  "hexuronic  acid"  which  possessed 
strong  antiscorbutic  properties.  The  announce- 
ment of  this  finding  was  followed  in  a  few  weeks 
by  the  report  of  Svirbely  and  Szent-Gyorgyi  that 
"hexuronic  acid"  as  prepared  from  adrenal  glands 
was  protective  against  scurvy.  Within  a  short 
period  of  time  several  workers  independently  con- 
firmed the  chemical  identity  of  the  vitamin  and 
in  1933  its  structural  formula,  as  a  lactone  of 
hexuronic  acid,  was  firmly  established.  Ascorbic 
acid  occurs  naturally  in  many  plants,  particularly 
in  the  fruits.  Asenjo  and  Guzman  {Science,  1946, 
103,  219)  have  reported  that  the  West  Indian 
cherry,  which  grows  on  small  trees  native  to 
tropical  and  subtropical  America,  yields,  on  the 
average,  1.707  Gm.  of  ascorbic  acid  per  100  Gm. 
of  cherries — approximately  34  times  as  much  as 
from  oranges. 

Even  before  the  chemical  structure  was  posi- 
tively known,  methods  for  the  synthesis  of  ascor- 
bic acid  had  been  worked  out.  Because  of  the 
relationship  of  the  acid  to  many  known  sugars 
and  their  derivatives,  various  syntheses  of  the 
former  utilize  the  latter  as  starting  compounds. 
The  first  synthesis  of  ascorbic  acid  used  the  rare 
sugar  L-xylose.  A  later  synthesis  starts  with 
D-glucose;  this  is  first  converted  to  the  alcohol 
D-sorbital  by  catalytic  hydrogenation,  then  oxi- 
dized through  the  action  of  Acetobacter  sub- 
oxydans  to  L-sorbose  (which  has  the  same  con- 
figuration at  the  fifth  carbon  atom  as  has  ascorbic 
acid),  following  which  the  primary  alcohol  group 
in  the  Ci  position  of  L-sorbose  is  oxidized  to  a 
carboxyl  group.  This  step  is  rendered  difficult 
because  the  L-sorbose  molecule  contains  another 
primary  alcohol  group  at  the  Ce  position;  this 
latter  group  must  be  protected  against  oxidation 
by  converting  the  sugar  to  a  diacetone  derivative. 


116 


Ascorbic  Acid 


Part  I 


Following  the  oxidation  (with  potassium  perman- 
ganate), the  diacetone  derivative  is  hydrolyzed  to 
2-keto-L-gulonic  acid  and  finally  subjected  to 
enolization  and  formation  of  the  lactone  ring  to 
produce  ascorbic  acid. 

A  number  of  sugar  derivatives  having  struc- 
tures analogous  to  that  of  ascorbic  acid,  as  well 
as  stereoisomers  of  the  latter,  exhibit  antiscor- 
butic action,  but  in  no  case  does  the  activity  ap- 
proach that  of  ascorbic  acid.  It  appears  certain 
that  antiscorbutic  activity  is  contingent  on  hav- 
ing the  D-configuration  of  the  fourth  carbon  atom 
in  the  molecule  and  the  L-configuration  of  the 
fifth  carbon  atom. 

Description. — "Ascorbic  Acid  occurs  as  white 
or  slightly  yellow  crystals  or  powder.  It  is  odor- 
less, and  on  exposure  to  light  it  gradually  darkens. 
In  the  dry  state,  Ascorbic  Acid  is  reasonably 
stable  in  the  air,  but  in  aqueous  solution  it  rapidly 
deteriorates  in  the  presence  of  air.  It  melts  at 
about  190°.  One  Gm.'  of  Ascorbic  Acid  dissolves 
in  about  3  ml.  of  water  and  in  about  30  ml.  of 
aicohol;  it  is  insoluble  in  chloroform,  in  ether, 
and  in  benzene."  U.S.P.  The  B.P.  gives  the  melt- 
ing point  as  between  190°  and  192°,  with  decom- 
position; the  I. P.  requires  it  to  be  between  191° 
and  194°,  with  decomposition. 

Standards  in  Tests. — Optical  rotation. — The 
specific  rotation  of  ascorbic  acid,  determined  with 
a  10  per  cent  w/v  solution,  is  between  +20.5° 
and  +21.5°.  Identification. — (1)  Alkaline  cupric 
tartrate  T.S.  is  slowly  reduced  by  a  1  in  50  solu- 
tion of  ascorbic  acid  at  room  temperature,  more 
readily  when  heated.  (2)  A  blue  color  is  immedi- 
ately produced  on  adding  a  few  drops  of  sodium 
nitroprusside  T.S.  and  1  ml.  of  0.1  N  sodium 
hydroxide  to  2  ml.  of  a  1  in  50  solution  of  ascorbic 
acid.  (3)  A  blue  color  develops  on  heating  with 
a  drop  of  pyrrole  5  ml.  of  filtrate  obtained  from 
a  well-shaken  mixture  of  15  mg.  of  ascorbic  acid, 
dissolved  in  15  ml.  of  a  1  in  20  solution  of  tri- 
chloroacetic acid,  with  200  mg.  of  activated  char- 
coal. Residue  on  ignition. — Not  over  0.1  per  cent. 
Heavy  metals. — The  limit  is  20  parts  per  million. 
U.S.P. 

The  B.P.  requires  an  aqueous  solution  of  ascor- 
bic acid  to  decolorize  a  solution  of  2:6-dichloro- 
phenolindophenol.  The  specific  rotation  of  a  2 
per  cent  w/v  solution  is  stipulated  as  follows: 
22°  to  23°  in  water;  50°  to  51°  in  methyl  alcohol. 
The  I. P.  specifices  an  ultraviolet  absorbancy  of 
550  in  a  0.002  per  cent  w/v  aqueous  solution  of 
pH  3,  or  less,  at  245  mix. 

Preparation  of  Solutions  of  Ascorbic 
Acid. — It  has  long  been  known  that  prolonged 
boiling  would  destroy  the  antiscorbutic  value  of 
fresh  foods,  and  it  was  at  one  time  believed  that 
this  vitamin  was  heat-labile,  but  it  is  now  known 
that  the  destruction  of  the  vitamin  is  an  oxidative 
process;  ascorbic  acid  can  be  heated  for  long 
periods  of  time  without  change,  provided  all 
contact  with  oxygen  is  excluded.  The  products  of 
oxidation  of  ascorbic  acid  in  aqueous  solution 
depend  in  part  on  the  pH  of  the  solution;  in  acid 
solutions  the  main  product  is  dehydroascorbic  acid 
while  in  alkaline  solution  hydrogen  peroxide,  oxa- 
.late  ion  and  L-threonate  ion  are  formed.  (J.A.C.S., 


1943,  65,  1212).  It  is  reported  that  solutions 
containing  10  per  cent  or  more  of  ascorbic  acid 
sometimes  undergo  a  decomposition  in  which 
carbon  dioxide  is  produced,  and  in  such  amount 
that  dangerously  high  pressure  may  result  in 
ampuls  during  normal  storage.  Unless  oxygen  is 
kept  out  of  contact  with  aqueous  solutions  of 
ascorbic  acid,  or  an  antioxidant  is  used,  the  vita- 
min cannot  be  expected  to  remain  stable.  Pien 
and  Meinrath  (Compt.  rend.  acad.  sc,  1939,  209, 
462)  found  that  displacement  of  oxygen  by  carbon 
dioxide  or  nitrogen  in  aqueous  solutions  of  as- 
corbic acid  results  in  their  retaining  nearly  90  per 
cent  activity  after  20  minutes  heating  in  an  auto- 
clave. Some  decomposition  occurs  also  in  the 
absence  of  oxygen,  especially  so  if  the  solution 
is  alkaline.  U.  S.  Patent  2,297,212  discloses  that 
the  addition  of  thiourea  (or  its  methyl  or  ethyl 
derivative)  in  concentrations  of  0.005  per  cent  is 
effective  in  stabilizing  ascorbic  acid  solutions ;  the 
thiourea  is  harmless.  The  stabilizing  effect  of 
sodium  chloride  has  also  been  reported,  Vonesch 
and  Remezzano  (Chem.  Abs.,  1942,  36,  217) 
stating  that  addition  of  3  parts  of  sodium  chloride 
for  each  10  parts  of  ascorbic  acid  sufficed  to  retard 
oxidation  materially.  Non-aqueous  solvents,  such 
as  propylene  glycol,  are  sometimes  used  with 
water  in  preparing  injectable  solutions  of  ascorbic 
acid.  For  data  on  the  stability  of  ascorbic  acid  in 
various  liquid  formulations  see  Bandelin  and 
Tuschhoff  (/.  A.  Ph.  A.,  1955.  44,  241). 

Aqueous  solutions  of  ascorbic  acid,  more  prop- 
erly referred  to  as  solutions  of  sodium  ascorbate, 
may  be  prepared  by  the  interaction  of  stoichio- 
metric quantities  of  ascorbic  acid  and  sodium 
bicarbonate,  while  carbon  dioxide  is  being  passed 
through  the  solution;  the  pH  of  the  solution 
should  be  adjusted  to  within  6.8  to  7.0  by  the 
addition  of  ascorbic  acid  or  sodium  bicarbonate, 
as  required.  When  required,  a  mixture  of  0.09  per 
cent  of  methylparaben  and  0.01  per  cent  of 
propylparaben  may  be  used  as  bacteriostatic 
agents.  Ampuls  may  be  sterilized  at  120°  for  15 
minutes.  Ciminera  and  Wilcox  (/.  A.  Ph.  A., 
1946,  35,  363)  found  that  a  solution  of  ascorbic 
acid,  adjusted  to  a  pH  of  6.0  to  6.5  with  trisodium 
phosphate  and  protected  from  air  during  manipu- 
lation, was  stable  for  at  least  one  year  at  room 
temperature  in  the  dark. 

Assay. — The  U.S. P.  directs  that  about  400  mg. 
of  ascorbic  acid,  previously  dried  in  a  vacuum 
desiccator  over  sulfuric  acid  for  3  hours,  be 
titrated  with  0.1  A7  iodine  in  an  acid  solution; 
each  molecule  of  ascorbic  acid  reacts  with  a  mole- 
cule of  iodine  to  form  dehydroascorbic  acid  and 
two  iodide  ions.  Each  ml.  of  0.1  N  iodine  repre- 
sents 8.806  mg.  of  CeHgOe.  U.S.P.  Bandaruk 
(Am.  J.  Pharm.,  1941,  113,  18)  and  later  Goett 
et  al.  (J.  A.  Ph.  A.,  1943,  31,  7)  advocated  titra- 
tion with  potassium  iodate  solution  as  giving  a 
more  satisfactory  end-point  than  obtained  with 
iodine  solution. 

The  B.P.  assay  utilizes  the  same  reaction  as 
employed  in  the  U.S.P.  except  that  the  former 
directs  titration  of  a  40-mg.  sample  with  0.01  N 
iodine  solution.  The  LP.  assay  employs  about 
900  mg.  of  ascorbic  acid,  neutralizes  it  with  0.1  N 


Part  I 


Ascorbic  Acid 


117 


sodium  hydroxide  in  the  presence  of  phenol- 
phthalein,  adds  50  ml.  of  0.1  N  iodine  and  titrates 
the  excess  iodine  with  0.1  N  sodium  thiosulfate. 

The  facility  with  which  ascorbic  acid  is  oxidized 
to  dehydroascorbic  acid  is  the  basis  of  several 
other  chemical  assay  procedures.  Besides  iodine, 
ascorbic  acid  will  reduce  ferricyanides,  copper 
sulfate,  methylene  blue,  etc.  Perhaps  the  most 
important  method  of  determining  ascorbic  acid 
in  natural  products  is  that  involving  decoloriza- 
tion  of  the  dye  dichlorophenolindophenol.  For  a 
description  of  this  assay,  which  is  also  applied  to 
the  official  tablets,  see  Bessey,  J.A.M.A.,  1938, 
111,  1291.  Schmall  et  al.  {Anal.  Chem.,  1954,  26, 
1521)  recently  described  a  new  method  for  the 
colorimetric  determination  of  ascorbic  acid,  this 
depending  on  its  interaction  with  diazotized  4- 
methoxy-2-nitroaniline,  the  product  having  a 
stable  blue  color  in  alkaline  solution. 

Uses. — Scurvy. — The  disease  known  as  scurvy, 
for  centuries  one  of  the  major  plagues  of  human- 
ity, especially  in  areas  where  the  populace  has 
been  unable  to  obtain  fresh  fruit  or  vegetables, 
is  caused  by  a  lack  of  ascorbic  acid.  Frank  scurvy 
is  less  frequent  now  than  formerly;  in  the  United 
States  it  is  seen  in  infants  (Follis  et  al.,  Bull. 
Johns  Hopkins  Hosp.,  1950,  87,  569)  and  in 
indigent  old  men  living  alone.  Most  lower  forms 
of  animals  appear  to  be  able  to  synthesize  ascorbic 
acid,  but  guinea  pigs  and  primates  must  ingest 
this  essential  substance  in  their  food  supply.  The 
amount  of  ascorbic  acid  in  a  diet  of  cow's  milk 
(about  0.7  mg.  per  100  ml.  of  milk)  is  insufficient 
for  either  an  infant  or  an  adult  with  peptic  ulcer; 
milk  from  a  well-nourished  woman  contains  the 
adequate  amount  of  approximately  5.2  mg.  per 
100  ml. 

The  outstanding  symptoms  of  scurvy  are  great 
fragility  of  the  blood  capillaries  (Hines  and 
Parker,  Quart.  Bull.  Northwest  U.  Med.  Sch., 
1949,  23,  424),  as  shown  by  a  tendency  to  ex- 
ternal or  internal  hemorrhage  on  the  slightest 
injury,  improper  development  of  the  teeth  or 
periodontal  hemorrhage  and  inflammation  after 
eruption  of  teeth,  and  great  muscular  weakness. 
The  underlying  pathology  is  a  change  in  the  char- 
acter of  the  intercellular  matrix  of  the  connective 
tissues  (Dalldorf,  J. A.M. A.,  1938,  111,  1376). 
Fibroblasts  and  ground  substance  are  formed,  but 
collagen,  osteoid  tissue  and  dentine  fail  to  form 
(Follis,  Bull.  Johns  Hopkins  Hosp.,  1951,  89,  9). 
Severe  deficiency  of  ascorbic  acid  may  occur  in 
surgical  conditions  and  result  in  disruption  of 
wounds  {New  Eng.  J.  Med.,  1942,  226,  469;  Am. 
J.  Surg.,  1944,  66,  220),  and  failure  of  union  of 
fractures  {Proc.  Roy.  Soc.  Med.,  1944,  37,  275). 
Scorbutic  patients  often  show  evidence  of  de- 
generation of  skeletal  muscles,  anemia,  enlarge- 
ment of  the  heart,  atrophy  of  the  adrenals, 
lowered  resistance  to  infection,  and  disturbances 
of  calcium  metabolism.  Roentgen  examination 
often  shows  subperiosteal  hemorrhages,  broad 
epiphyses  and  interruptions  in  the  lamina  dura  of 
the  teeth.  Physicians  always  look  for  swollen, 
spongy,  interdental  papillae,  of  a  blue  or  brown- 
red  color,  which  bleed  easily,  as  a  sign  of  scurvy, 
although   McMillan   and   Inglis    {Brit.   Med.   J., 


1944,  2,  233)  reported  gingivitis  in  only  8  of  53 
cases  of  scurvy. 

A  megaloblastic  anemia  in  infants  was  described 
by  Zuelzer  and  Ogden  {Am.  J.  Dis.  Child.,  1946, 
71,  211)  which  responded  to  treatment  with  folic 
acid  but  not  to  iron  or  the  vitamin  B12  in  liver 
extract.  Analysis  of  the  reported  cases,  and  feed- 
ing experiments  on  monkeys,  demonstrated  that 
vitamin  C  deficiency  in  the  diet  of  the  infant  was 
responsible  for  the  megaloblastic  type  of  anemia 
(May  et  al,  ibid.,  1950,  80,  191;  1952,  82,  282). 
Treatment  with  ascorbic  acid  corrected  the  me- 
galoblastic bone  marrow  and  the  anemia  slowly. 
If  vitamin  B12  was  injected  intramuscularly,  cor- 
rection was  as  rapid  as  with  administration  of 
folic  acid  by  mouth. 

Physiological  Function. — The  physiological 
role  of  ascorbic  acid  is  beginning  to  unfold. 
Sealock  and  Goodland  {Science,  1951,  114,  645) 
reported  that  ascorbic  acid  is  an  essential  co- 
enyme  in  the  metabolic  oxidation  of  tyrosine  and 
phenylalanine.  Scorbutic  guinea  pigs  and  humans 
excrete  homogentisic  acid  and  other  hydroxy- 
phenyl  compounds  in  the  urine;  oxidation  of  the 
phenyl  nucleus  seems  to  require  ascorbic  acid 
(Rogers  and  Gardner,  /.  Lab.  Clin.  Med.,  1949, 
34,  1491).  Urinary  excretion  of  p-hydroxyphenyl- 
pyruvic  acid  and  />-hydroxyphenyllactic  acid  in 
premature  infants  is  corrected  by  administration 
of  ascorbic  acid.  Histochemical  studies  of  experi- 
mental wound  healing  in  guinea  pigs  receiving 
vitamin  C  demonstrate  the  presence  of  an  acid 
mucopolysaccharide  in  the  early  days  of  healing 
which  is  shown  by  incubation  with  hyaluronidase 
to  be  hyaluronic  acid  or  chondroitin  sulfate;  this 
ground  substance  is  not  found  in  wounds  of 
scorbutic  animals  (Penney  and  Balfour,  /.  Path. 
Bad.,  1949,  61,  171).  An  abnormal  mucopoly- 
saccharide and  an  abnormal  precollagen  have  been 
found  in  such  wounds  (Bradfield  and  Kodicek, 
Biochem.  J.,  1951,  49,  xvii).  Even  six  weeks  after 
receiving  an  experimental  wound  well-nourished 
guinea  pigs,  with  good  gross  and  microscopic  evi- 
dence of  fibrotic  healing,  when  fed  for  18  days 
on  a  vitamin  C-deficient  diet  developed  swelling, 
herniation  and  hemorrhage  in  the  scars,  with  his- 
tologic evidence  of  degenerative  changes,  although 
the  overlying  epithelium  and  the  adjacent  con- 
nective tissue  appeared  normal  (Pirani  and  Leven- 
son,  Proc.  S.  Exp.  Biol.  Med.,  1953,  82,  95).  Even 
maintenance  of  a  recent  scar  seems  to  require 
adequate  amounts  of  vitamin  C.  An  increase  in 
the  blood  serum  concentration  of  glycoproteins 
was  observed  in  scorbutic  guinea  pigs  by  Pirani 
{Arch.  Path.,  1951,  51,  597);  administration  of 
ascorbic  acid  is  followed  by  a  return  to  a  normal 
concentration.  It  is  suggested  that  ascorbic  acid 
deficiency  results  in  a  depolymerization  of  carbo- 
hydrate-containing constituents  of  the  ground 
substance  of  connective  tissue,  with  absorption  of 
the  smaller  molecule  into  the  blood  stream.  Rep- 
pert  et  al.  {Proc.  S.  Exp.  Biol.  Med.,  1951,  77, 
318)  believe  that  ascorbic  acid  may  inhibit  the 
hyaluronidase-hyaluronic  acid  system  in  inter- 
stitial substance;  loss  of  support  for  the  capil- 
laries from  the  surrounding  ground  substance 
would  be  expected  to  increase  capillary  fragility. 


118 


Ascorbic  Acid 


Part  I 


Daubenmerkl  (Acta  Pharmacol.  Toxicol.,  1951, 
7,  153)  observed  that  ascorbic  acid,  in  minute 
concentrations  in  vitro,  decreased  the  viscosity  of 
hyaluronic  acid  solutions  at  pH  7;  with  higher 
concentrations  of  ascorbic  acid  this  depolymeriz- 
ing  action  was  augmented  and  accelerated  by  the 
addition  of  hydrogen  peroxide  and  such  a  mixture 
was  an  effective  "spreading  factor"  for  adminis- 
tration of  fluids  by  hypodermoclysis  in  children. 
For  clinical  purposes  this  spreading  factor  is  less 
desirable  than  hyaluronidase  because  of  some 
irritation  and  the  necessity  for  regulating  the  dose 
within  narrow  limits. 

In  line  with  the  observations  of  Moon  and 
Rhinehart  (Circulation,  1952,  6,  481),  Duff  (Arch. 
Path.,  1935,  20,  371)  and  Aschoff,  that  the  initial 
lesion  in  atherosclerosis  is  an  alteration  in  the 
intercellular  ground  substance  of  the  artery, 
Willis  (Can.  Med.  Assoc.  J.,  1953,  69,  17)  re- 
ported some  thought-provoking  observations. 
Atherosclerosis  was  found  in  guinea  pigs  with 
acute  or  chronic  scurvy  and  with  normal  blood 
cnolesterol  levels  and  without  lipid  deposits  in 
the  reticuloendothelial  system;  this  simulates 
human  atherosclerosis  more  than  does  the  ex- 
perimental cholesterosis  in  rabbits  or  chickens  fed 
large  amounts  of  fat  and  cholesterol. 

Adrenals,  Stress  and  Ascorbic  Acid. — The 
rapid  depletion  of  ascorbic  acid  in  almost  any 
severe  illness  has  long  been  recognized.  For  ex- 
ample, the  concentration  in  blood  and  urine 
drops  rapidly  to  low  levels  in  severe  burns 
(Levenson  et  al.,  Ann.  Surg.,  1946,  124,  840). 
Furthermore,  a  large  dose  of  ascorbic  acid  in  such 
a  patient  is  not  excreted  but  is  retained  in  the 
body,  to  be  destroyed  or  utilized.  The  high  con- 
centration of  ascorbic  acid  in  the  adrenal  gland, 
along  with  its  rapid  increase  (as  well  as  of  cho- 
lesterol) following  administration  of  corticotropin 
or  application  of  stress,  have  resulted  in  con- 
siderable study  of  the  relationship  of  adrenal 
corticoids  and  ascorbic  acid  (Sayers,  Physiol. 
Rev.,  1950,  30,  241).  The  mechanism  of  this 
relation  is  apparently  not  to  be  found  in  the 
adrenal  gland  since  no  evidence  of  deficiency  in 
adrenal  corticoids  can  be  found  in  scorbutic 
humans  or  animals  (see  Nutr.  Rev.,  1954,  12, 
81).  In  fact,  blood  and  urine  levels  of  17-hydroxy- 
corticoids  are  increased  in  scurvy,  and  studies 
with  carbon-  14-labeled  acetate  in  animals  showed 
greater  conversion  to  adrenal  cholesterol  than  in 
well-nourished  animals  which  served  as  a  control 
(Becker  et  al,  J.A.C.S.,  1953,  75,  2020).  An  in- 
creased urinary  excretion  of  corticoids,  but  not 
of  17-ketosteroids,  was  found  in  children  given 
both  corticotropin  and  ascorbic  acid  (Sprechler 
and  Vesterdal,  Acta  Endocrinol.,  1953,  12,  207). 
In  rats,  salicylates  cause  a  decrease  in  adrenal 
ascorbic  acid,  but  not  of  cholesterol  (Comulada 
et  al.,  Fed.  Proc,  1953,  12,  313). 

Metabolism. — Ascorbic  acid  is  not  stored  in 
the  body  to  any  considerable  extent.  In  the  ex- 
periments of  Crandon  (New  Eng.  J.  Med.,  1940, 
223,  353),  who  lived  on  a  diet  completely  lack- 
ing in  ascorbic  acid  but  adequate  in  all  other  sub- 
stances, the  blood  plasma  ascorbic  acid  fell  within 
.10  days  to  a  low  level  and  in  41  days  completely 


to  zero.  However,  the  concentration  of  ascorbic 
acid  in  the  leukocyte  and  platelet  layer  of  the 
blood  did  not  drop  to  zero  until  130  days.  Hyper- 
keratotic  papules  appeared  on  the  thighs  after  132 
days  and  perifolicular  hemorrhage  after  161  days. 
An  incision  in  the  skin  healed  normally  after  95 
days  on  the  diet,  when  the  blood  plasma  level  of 
ascorbic  acid  was,  and  had  been,  zero  for  44  days, 
but  the  white  cell-platelet  layer  contained  4  mg. 
of  ascorbic  acid  per  100  Gm.  After  160  days 
clinical  scurvy  was  present  and  an  incision  did  not 
heal  until  ascorbic  acid  was  given.  Pijoan  and 
Lozner  (Bull.  Johns  Hopkins  Hosp.,  1944,  75, 
303)  confirmed  Crandon's  findings. 

A  portion  of  the  ascorbic  acid  ingested  with  the 
normal  diet  appears  to  be  destroyed  in  the  body 
but  a  greater  part  is  excreted.  The  rate  of  excre- 
tion in  the  urine  affords  a  criterion  of  the  amount 
in  the  blood.  The  renal  threshold  is  about  1.4  mg. 
per  100  ml.  of  plasma  (Arch.  Int.  Med.,  1945,  75, 
407).  Ascorbic  acid  is  excreted  in  sweat,  but 
Henschel  and  his  associates  (Am.  J.  Trop.  Med., 
1944,  24,  259)  believe  this  to  be  negligible  and 
found  no  evidence  for  an  increased  requirement 
for  vitamin  C  in  hot  environments.  Although 
Crandon  and  others  have  shown  that  less  than 
25  mg.  of  ascorbic  acid  per  100  Gm.  in  the  white 
cell-platelet  layer  of  the  blood  is  a  better  criterion 
of  deficiency  than  a  decrease  in  the  blood  plasma 
level,  Kyhos,  Sevringhaus  and  Hagedorn  (Arch. 
Int.  Med.,  1945,  75,  407)  reported  that  persons, 
sick  or  well,  who  regularly  ingest  adequate 
amounts  of  vitamin  C-containing  food  seldom  have 
fasting  blood  plasma  values  lower  than  0.8  mg. 
per  100  ml.  They  do  not  believe  that  determina- 
tions of  ascorbic  acid  in  whole  blood  are  superior 
to  determinations  in  plasma.  The  disagreement 
continues.  After  depletion  of  normal  adult  humans 
with  a  daily  intake  of  10  mg.  of  ascorbic  acid  or 
less  to  three-fourths  to  one-half  of  the  initial 
concentration  in  white  blood  cells,  Steele  et  al. 
(Fed.  Proc,  1953,  12,  430)  found  that  a  daily 
intake  of  40  mg.,  but  not  of  20  or  even  30  mg., 
caused  an  increase  in  the  white  blood  cell  content 
of  ascorbic  acid,  with  a  persistently  low  plasma 
concentration  of  0.2  mg.  per  100  ml.  Lutz  et  al. 
(ibid.,  1954,  13,  466)  reported  that  subjects 
saturated  with  ascorbic  acid  from  a  period  of 
large  daily  intake  failed  to  maintain  their  high 
concentration  in  the  white  blood  cells  on  a  daily 
intake  of  40  mg.;  depleted  subjects,  however,  did 
maintain  their  initial  subnormal  concentration  on 
this  daily  intake.  The  minimum  normal  blood 
plasma  ascorbic  acid  concentration  is  0.8  mg.  per 
100  ml.  In  many  persons  the  concentration  is 
slightly  lower  in  the  spring  of  the  year  as  a  result 
of  the  lower  intake  of  fresh  fruits  and  vegetables 
during  the  winter  period. 

Optimal  Nutritional  Requirement. — In  nor- 
mal conditions  the  daily  requirement  for  main- 
tenance of  optimal  health  in  the  adult  male  is 
given  as  75  mg.  by  the  National  Research  Council 
(U.S.A.).  The  Canadian  Council  on  Nutrition 
(Can.  Pub.  Health  J.,  1949,  40,  420),  however, 
recommended  30  mg.  daily  as  adequate.  On  the 
basis  of  the  incidence  of  illness  in  a  controlled 
population,  Scheunert  (Intern.  Ztschr.  Vitamin- 


Part  I 


Ascorbic  Acid 


119 


forsch.,  1949,  20,  374)  reported  that  100  or  even 
300  mg.  is  to  be  preferred.  The  recommended 
daily  dietary  allowances  of  the  National  Research 
Council  (U.S.A.)  are  as  follows:  man  (65  Kg.), 
75  mg.;  woman  (55  Kg.),  70  mg.;  during  preg- 
nancy (third  trimester),  100  mg.;  during  lacta- 
tion, 150  mg.;  infants,  30  mg.;  children  (1  to 
3  years  old),  35  mg.;  children  (4  to  6  years  old), 
50  mg.;  children  (7  to  9  years  old),  60  mg.;  chil- 
dren (10  to  12  years  old),  75  mg.;  girls  from  13 
to  20  years  old,  80  mg.;  boys  from  13  to  20  years 
old,  90  to  100  mg. 

These  recommendations  find  confirmation  in 
the  report  of  Wilson  and  Lubschez  (/.  Clin.  Inv., 
1946,  25,  428)  that  from  50  to  75  mg.  was  the 
amount  required  daily  by  normal  children  averag- 
ing seven  years  of  age  to  maintain  a  level  of  25 
mg.  per  cent  of  ascorbic  acid  in  the  white  cell- 
platelet  layer.  They  believe  this  level  to  be  a 
better  criterion  of  habitual  intake  of  the  vitamin 
than  either  plasma  or  urine  levels.  It  is  claimed 
that  a  very  considerable  proportion  of  the  popula- 
tion is  suffering  from  subclinical  scurvy,  that  is, 
from  a  partial  deficiency  of  ascorbic  acid 
(J.A.M.A.,  1942,  118,  944).  From  1.4  to  1.8  mg. 
per  Kg.  of  body  weight  was  required  daily  by 
young  women  to  produce  saturation  with  the 
vitamin  as  evidenced  by  urinary  excretion  of  50 
per  cent  of  a  test  dose  of  400  mg.  orally  (Kline 
and  Eheart,  /.  Nutrition,  1944,  28,  413).  How- 
ever, both  Crandon  (loc.  cit.)  and  Pijoan  and 
Lozner  (New  Eng.  J.  Med.,  1944,  231,  14) 
showed  that  saturation,  as  evidenced  by  overflow 
in  the  urine,  is  not  essential  for  health;  from  12 
to  25  mg.  of  ascorbic  acid  daily  maintained  a 
normal  concentration  in  the  white  cell-platelet 
layer  and  permitted  normal  wound  healing.  Najjar 
et  al.  (Bull.  Johns  Hopkins  Hosp.,  1944,  75,  315) 
confirmed  the  adequacy  of  18  to  25  mg.  of  ascor- 
bic acid  daily  for  young  adults.  In  20-year-old 
male  students  in  Iceland  habitually  on  a  diet  of 
about  20  mg.  ascorbic  acid  daily,  Sigurjonsson 
(Brit.  J.  Nutrition,  1951,  5,  216)  studied  the 
urinary  excretion  when  10  mg.  per  Kg.  per  day 
was  fed.  A  maximum  output  of  50  to  60  per  cent 
of  the  dose  was  reached  on  the  second  or  third 
day,  decreasing  thereafter  despite  continuation  of 
the  high  intake;  this  suggests  an  increased  rate 
of  destruction.  A  diuretic  effect  has  been  reported 
in  man  following  large  doses  (700  mg.)  by  mouth, 
but  not  intravenously;  ascorbic  acid  has  been 
used  effectively  in  the  treatment  of  edema 
(Shaffer,  J. A.M. A.,  1944,  124,  700). 

Therapeutic  Uses. — Ascorbic  acid  is  used  as 
a  specific  curative  in  scurvy.  In  many  different 
diseases  a  deficiency  of  the  vitamin  may  develop 
due  to  anorexia,  to  fault  of  a  special  diet,  to 
failure  of  absorption  as  in  diarrheal  and  other 
disorders,  or  to  increased  requirements  in  hyper- 
metabolism (Proc.  S.  Exp.  Biol.  Med.,  1938,  39, 
233;  Bull.  Johns  Hopkins  Hosp.,  1938,  63,  31) 
or  during  the  course  of  infections.  The  correction, 
or  better  the  prevention,  of  any  deficiency  of 
ascorbic  acid  will  benefit  such  patients. 

Detoxification. — Ascorbic  acid  has  a  detoxify- 
ing action  toward  many  toxins,  drugs  and  indus- 
trial chemicals  (J. A.M. A.,  1943,  121,  868;  Arch. 


Int.  Med.,  1943,  71,  315).  Thus,  it  is  of  value 
in  connection  with  arsenicals,  such  as  neoarsphen- 
amine  (J. A.M. A.,  1941,  117,  1692;  Am.  J.  Digest. 
Dis.,  1943,  10,  170;  /.  Pharmacol,  1944,  80, 
81),  benzene  and  trinitrotoluene  (J  -Lancet,  1943, 
63,  349),  bismuth  and  antimony  compounds  (Am. 
J.  Digest.  Dis.,  1943,  10,  170),  the  sulfonamides 
(Arch.  Int.  Med.,  1942,  69,  662),  intravenous 
procaine  hydrochloride  (J.A.M.A.,  1951,  147, 
1761);  Arch.  Dermat.  Syph.,  1952,  65,  39), 
salicylates  (/.  Lab.  Clin.  Med.,  1942,  28,  28), 
diethylstilbestrol  (J.A.M.A.,  1943,  123,  113), 
gold  salts  (New  Eng.  J.  Med.,  1943,  229,  773; 
J.A.M.A.,  1942,  120,  1331),  and  lead  (/.  Lab. 
Clin.  Med.,  1941,  26,  1478).  However,  the  bene- 
ficial effect  in  lead  poisoning  has  been  denied 
(J. A.M. A.,  1943,  121,  501).  The  hypnotic  action 
of  phenobarbital  or  pentobarbital  is  greater  in 
scorbutic  guinea  pigs  (/.  A.  Ph.  A.,  1941,  30, 
613);  Greig  (/.  Pharmacol,  1947,  91,  317)  de- 
scribed a  depression  of  oxidative  metabolism  in 
the  brain  by  barbiturates  which  was  corrected, 
in  vitro,  with  ascorbic  acid.  McCormick  (Arch. 
Pediat.,  1953,  70,  107)  recommended  use  of 
ascorbic  acid  to  minimize  the  alleged  undesirable 
results  to  be  expected  from  drinking  public  water 
supplies  to  which  fluoride  has  been  added  in  a 
"misguided"  effort  to  prevent  dental  caries.  Bour- 
quin  and  Musmanno  (Am.  J.  Digest.  Dis.,  1953, 
20,  75)  found  that  smoking  of  cigarettes  or 
addition  of  nicotine  to  blood,  in  vitro,  decreased 
the  concentration  of  ascorbic  acid  in  blood.  In- 
travenous injection  of  1  Gm.  of  sodium  ascorbate 
at  the  time  that  a  patient  taking  tetraethyl- 
thiuram disulfide  is  given  ethyl  alcohol  relieved 
headache,  restlessness,  palpitation,  weakness  and 
apprehension  but  did  not  prevent  the  increase  in 
acetaldehyde  concentration  in  blood  or  the  hypo- 
tension, tachycardia  and  flushing  of  the  skin 
(Niblo  et  al,  Dis.  Nerv.  System,  1951,  12,  340). 
Greiner  and  Gold  (J. A.M. A.,  1953,  152,  1130) 
did  not  find  any  decrease  in  the  incidence  of  un- 
toward effects  when  ascorbic  acid  was  added  to 
meralluride  administered  by  mouth  as  a  diuretic. 
Treatment  of  Various  Disorders. — Ascorbic 
acid,  being  related  to  the  functioning  of  inter- 
cellular substance,  has  come  into  consideration  in 
all  phases  of  physiology  and  pathology  and  has 
been  tried  in  the  treatment  of  almost  all  of  the 
disorders  of  mankind.  Benefit  has  been  reported 
in:  retinal  hemorrhage  (Am.  J.  Obst.  Gyn.,  1943, 
46,  635),  coronary  thrombosis  (Can.  Med. 
Assoc.  J.,  1941,  44,  114),  hematuria  (/.  Urol, 
1939,  41,  401),  bleeding  peptic  ulcer  (Ann.  Int. 
Med.,  1940,  14,  588),  peptic  ulcer  without  hem- 
orrhage (Am.  Pract.,  1952,  3,  117),  rheumatic 
fever,  diphtheria,  pneumonia  and  scarlet  fever 
(Am.  J.  Dis.  Child.,  1942,  64,  426),  acute  rheu- 
matic fever  (New  Eng.  J.  Med.,  1950,  242,  614) 
(in  doses  of  1  Gm.  by  mouth  4  times  daily), 
healing  of  deep  but  not  of  superficial  corneal 
ulcers  (Brit.  M.  J.,  1950,  2,  1145),  tuberculosis 
(Am.  Rev.  Tuberc,  1941,  44,  596),  grippe 
(Laryn.,  1938,  48,  327),  dysentery  (Clin.  Proc, 
1943,  2,  65),  fractures  (Klin.-therap.  Wchnschr., 
1937,  16,  1313),  prickly  heat  rash  on  the  skin 
(J.A.M.A.,  1951, 145, 175),  march  hemoglobinuria 


120 


Ascorbic  Acid 


Part   I 


(Lancet,  1949,  1,  435),  and  dental  caries  (Ann. 
Int.  Med.,  1944,  20,  1).  The  relation  of  ascorbic 
acid  to  gastrointestinal  disease  seems  to  have  sig- 
nificance. Freeman  and  Hafkesbring  (Fed.  Proc, 
1954,  13,  48)  found  that  both  blood  and  gastric 
juice  ascorbic  acid  concentrations  were  about  one- 
half  that  of  healthy  persons  in  patients  with  peptic 
ulcer,  gastritis,  pernicious  anemia,  and  carcinoma 
of  the  stomach.  The  studies  of  Breidenbach  and 
Roy  (ibid.,  1953,  12,  182)  indicated  that  ascorbic 
acid  retarded  proteolysis  in  mixtures  with  crude 
gastric  juice;  in  cases  of  peptic  ulcer  such  an 
action  would  minimize  the  concentration  of  acid 
and  pepsin  acting  on  the  gastric  mucosa. 

The  value  of  ascorbic  acid  in  the  following  con- 
ditions, among  others,  is  controversial:  hay  fever 
(Ann.  Allergy,  1949,  7,  65),  fatigue  (J. -Lancet, 
1943,  63,  355),  hot  environment  (Science,  News 
Sup.,  June  19,  1942,  p.  12;  but  see  /.  Allergy, 
1945,  16,  14),  and  bleeding  gums  and  gingivitis 
(Am.  J.  Pharm.,  1943,  115,  238;  Lancet,  1943, 

I,  640;  but  see  Am.  J.  Obst.  Gyn.,  1951,  61, 
1348;  /.  A.  Dent.  A.,  1944,  31,  1323),  in  com- 
bination with  menadione  in  hyperemesis  gravi- 
darum (Am.  J.  Obst.  Gyn.,  1952,  64,  416),  in 
combination  with  procaine  hydrochloride  orally 
in  pruritus  in  allergic  patients  (Ann.  Allergy,  1953. 

II,  85),  in  virus  infections  in  children  (measles, 
mumps,  chicken  pox,  pneumonia,  encephalitis  and 
poliomyelitis)  (South.  Med.  Surg.,  1951,  113, 
101),  and  intravenously  in  combination  with 
desoxycorticosterone  glucoside  for  temporary  re- 
lief in  rheumatoid  arthritis  (Lancet,  1952,  1, 
1280).  In  a  carefully  controlled  study  of  ascorbic 
acid  and  other  vitamins,  Cowan  et  al.  (J.A.M.A., 
1942,  120,  1268)  observed  no  benefit  in  the  pre- 
vention of  the  common  cold.  The  relationship 
between  the  blood  plasma  ascorbic  acid  level  and 
the  titer  of  complement  (J. A.M. A.,  1939,  112, 
1449)  was  not  confirmed  (/.  Immunol.,  1942,  44, 
289).  The  addition  of  ascorbic  acid  did  not  en- 
hance the  effect  of  ferrous  iron  therapy  in  ele- 
vating the  blood  hemoglobin  level  of  school  chil- 
dren (Brit.  M.  J.,  1944,  1,  76).  Ruskin  (Am.  J. 
Digest  Dis.,  1945,  12,  281),  in  experiments  on 
rabbit  bronchiolar  tissue,  demonstrated  ascorbic 
acid  to  have  antihistaminic  activity.  (Y) 

Toxicology. — Untoward  effects  from  either 
oral  use  or  proper  parenteral  administration  of 
appropriate  solutions  of  ascorbic  acid  are  almost 
unknown.  Cases  of  acute  hemolytic  anemia  in 
children  ingesting  a  solution  of  ^-aminosalicylic 
acid  containing  sodium  ascorbate  have  been  re- 
ported (Lust,  Scalpel,  1953,  106,  276;  abstracted 
in  J.A.M.A.,  1953,  152,  1281).  Lowry  et  al.  (Proc. 
S.  Exp.  Biol.  Med.,  1952,  80,  361)  fed  four  adult 
humans  1  Gm.  of  ascorbic  acid  daily,  in  three 
divided  portions  with  meals,  for  three  months 
without  untoward  symptoms,  and  with  no  altera- 
tion in  the  concentrations  of  the  vitamin  in  blood 
or  urine  at  the  end  of  the  period  as  compared 
with  the  first  few  weeks. 

Parenteral  Administration. — When  intes- 
tinal absorption  of  ascorbic  acid  is  inefficient  or 
when  a  massive  effect  is  desired  sodium  ascorbate 
may  be  injected  subcutaneously  or  intravenously 
.  (see  above  for  description  of  preparation  of  solu- 
tions of  the  salt).  Because  of  the  strong  acidity  of 


ascorbic  acid,  which  has  been  observed  to  cause 
an  increase  in  the  blood  pressure  of  animals,  the 
acid  itself  should  not  be  used  in  this  manner. 
Under  the  name  Cenolate  (Abbott)  a  methyl 
glucamine  salt  is  available  for  intravenous,  sub- 
cutaneous or  intramuscular  injection. 

Antioxidant  Action. — The  instability  of  as- 
corbic acid  in  the  presence  of  water  is  mainly 
attributable  to  the  ease  of  its  oxidation,  as  by  air. 
Because  of  this,  ascorbic  acid  may  serve  to  pre- 
vent oxidation  of  other  substances.  Since  ascorbic 
acid  is  available  in  large  quantities,  and  is  rela- 
tively inexpensive,  it  is  sometimes  used  for  this 
purpose.  One  ingenious  application  is  the  use  of 
ascorbic  acid  to  prevent  change  of  flavor  or  dis- 
coloration of  canned  or  frozen  fruits,  such  as  the 
peach;  150  mg.  of  the  acid  per  pound  of  fruit  is 
effective.  Development  of  rancidity  in  butter,  at 
37°,  was  found  to  be  retarded  by  addition  of  0.01 
per  cent  of  L-ascorbyl  stearate,  palmitate,  myris- 
tate  or  laurate  (Mukherjee  and  Goswami,  /.  In- 
dian Chem.  Soc,  1950,  27,  539;  see  also  Watts 
and  Wong,  Arch.  Biochem.,  1951,  30,  110). 

Dose. — The  usual  therapeutic  dose  of  ascorbic 
acid  is  150  mg.  (approximately  2l/2  grains)  daily, 
by  mouth,  or  by  subcutaneous  or  intravenous  ad- 
ministration of  sodium  ascorbate  injection;  the 
range  of  dose  is  100  mg.  to  1  Gm.  The  optimal 
daily  requirement  in  health  is  75  mg.  for  an  adult, 
with  a  range  of  25  to  75  mg.;  for  a  child  it  is 
50  mg.  daily.  An  infant  receiving  a  formula  of 
modified  cow's  milk  should  receive  5  mg.  daily. 
In  severe  illness  the  recommendation  of  Pijoan 
and  Lozner  (New  Eng.  J.  Med.,  1944,  231,  14) 
to  take  1  Gm.  daily  for  ten  days  is  worthwhile. 

The  dose  of  ascorbic  acid  was  formerly  ex- 
pressed in  terms  of  units.  The  U.S. P.  XII  defined 
its  unit  as  follows:  "One  United  States  Phar- 
macopoeial  Unit  of  Ascorbic  Acid  (Vitamin  C) 
is  the  Vitamin  C  activity  of  0.05  mg.  of  the  U.S. P. 
Reference  Standard,  and  is  equal  to  one  Interna- 
tional Unit  of  Vitamin  C  as  defined  and  adopted 
by  the  Conference  of  Vitamin  Standards  of  the 
Permanent  Commission  on  Biological  Standardiza- 
tion of  the  League  of  Nations  in  June  of  1934." 
U.S.P.  XII. 

Storage. — Preserve  "in  tight  containers." 
U.S.P. 

Off.  Prep. — Ascorbic  Acid  Tablets,  U.S.P., 
B.P.;  Decavitamin  Capsules;  Decavitamin  Tab- 
lets, U.S.P.;  Hexavitamin  Capsules;  Hexavitamin 
Tablets,  N.F. 

ASCORBIC  ACID  INJECTION.    U.S.P. 

Sodium  Ascorbate  Injection,  U.S.P.  XIV 

"Ascorbic  Acid  Injection  is  a  sterile  solution  of 
ascorbic  acid  in  water  for  injection  prepared  with 
the  aid  of  sodium  hydroxide,  sodium  carbonate,  or 
sodium  bicarbonate.  It  contains  not  less  than  95 
per  cent  and  not  more  than  115  per  cent  of  the 
labeled  amount  of  C6Hs06."  U.S.P. 

For  a  discussion  of  methods  of  preparing  this 
injection  see  the  preceding  monograph.  The 
U.S.P.  requires  the  pH  of  the  injection  to  be  be- 
tween 5.5  and  7.0.  The  assay  utilizes  the  method 
described  under  Ascorbic  Acid  Tablets. 

Storage. — Preserve  "in  single-dose  containers, 
preferably  of  Type  I  or  Type  II  glass."  U.S.P. 


Part  I 


Aspidium  121 


Usual  Sizes.— 100  and  500  mg.  in  2  ml.;  500 
mg.  and  1  Gm.  in  5  ml.;  500  mg.  in  10  ml. 

ASCORBIC  ACID  TABLETS. 

U.S.P.  (B.P.,  I.P.) 

Tabellas  Acidi  Ascorbici 

"Ascorbic  Acid  Tablets  contain  not  less  than 
95  per  cent  and  not  more  than  115  per  cent  of  the 
labeled  amount  of  CeHs06."  U.S.P.  The  corre- 
sponding limits  of  the  B.P.  are  88.0  per  cent  and 
110.0  per  cent;  the  I.P.  limits  are  90.0  and  110.0 
per  cent,  respectively. 

B.P.  Tablets  of  Ascorbic  Acid.  I.P.  Compressi  Acidi 
Ascorbici.  Sp.  Tabletas  de  Acido  Ascorbico. 

Assay. — Because  the  tablets  will  in  all  likeli- 
hood contain  other  substances,  besides  ascorbic 
acid,  which  reduce  iodine  it  is  not  possible  to  de- 
termine the  content  of  ascorbic  acid  in  the  tablets 
in  the  same  manner  as  the  pure  acid  is  analyzed. 
By  using  dichlorophenol-indophenol  solution,  how- 
ever, the  ascorbic  acid  may  be  oxidized — to  dehy- 
droascorbic  acid,  the  same  product  as  obtained  in 
the  titration  with  iodine — without  oxidizing  any 
other  constituent  that  may  normally  be  in  the 
tablet.  Dichlorophenol-indophenol  is  blue  in  alka- 
line solution,  pink  in  acid  and  colorless  when  it  is 
reduced.  For  this  titration  the  reagent  is  used  in 
alkaline  solution;  on  addition  to  the  ascorbic  acid 
solution  it  is  decolorized  and  the  end  point  is 
taken  to  be  the  appearance  of  a  rose-pink  color  in 
the  solution  which  persists  for  at  least  5  seconds. 
The  formation  of  the  pink  color  is  due  to  the  fact 
that  the  titration  medium  contains  acid,  which 
changes  the  blue  color  of  the  titrating  solution 
to  pink.  The  dichlorophenol-indophenol  solution 
is  standardized  against  pure  ascorbic  acid.  U.S.P. 

Ascorbic  acid  tablets  are  frequently  yellowish 
in  color  but  this  should  not  be  interpreted  as 
necessarily  indicating  extensive  decomposition. 
Such  discolored  tablets  may  readily  meet  the  offi- 
cial assay  requirement. 

Under  the  name  Sodascorbate  (Van  Patten) 
there  is  available  sodium  ascorbate,  in  tablets,  for 
use  in  all  conditions  for  which  ascorbic  acid  is 
given  orally.  The  sodium  salt  has  the  advantage 
of  minimizing  disturbance  which  may  be  caused 
by  the  acidity  of  ascorbic  acid,  especially  when 
large  doses  of  the  latter  are  given. 

Usual  Sizes.— 25,  50,  100,  250  and  500  mg. 

ASPIDIUM.     U.S.P.  (B.P,  I.P.) 

Male  Fern,   [Aspidium] 

"Aspidium  consists  of  the  rhizome  and  stipes 
of  Dryopteris  Filix-mas  (Linne)  Schott,  known  in 
commerce  as  European  Aspidium  or  Male  Fern, 
or  of  Dryopteris  marginalis  (Linne)  Asa  Gray, 
known  in  commerce  as  American  Aspidium  or 
Marginal  Fern  (Fam.  Polypodiacece) .  Aspidium 
yields  not  less  than  1.5  per  cent  of  crude  filicin." 
U.S.P. 

The  B.P.  recognizes  Male  Fern  as  the  rhizome, 
frond-bases  and  apical  bud  of  Dryopteris  filix-mas 
(L.)  Schott,  collected  late  in  the  autumn,  divested 
of  roots  and  dead  portions  and  carefully  dried, 
retaining  the  internal  green  color;  not  less  than 
1.50  per  cent  of  filicin  is  required.  The  I.P.  defi- 


nition and  requirement  of  filicin  content  are  prac- 
tically the  same  as  those  of  the  B.P.  except  that 
Dryopteris  marginalis  is  also  recognized  as  a 
source  of  the  drug. 

B.P.,  I.P.  Male  Fern;  Filix  Mas.  European  Aspidium; 
Basket  Fern.  Rhizoma  Filicis;  Filicis  Maris  Rhizoma.  Fr. 
Fougere  male.  Ger.  Farnwurzel ;  Johanniswurzel.  It.  Felce 
maschio.  Sp.  Rizoma  de  helecho  macho;  Aspidio. 

Since  the  term  Dryopteris  was  first  used  by 
Amman  in  1739,  and  applied  in  1763  by  Adam- 
son,  as  the  name  of  the  genus  to  which  the 
Aspidium  was  applied  in  1800  by  Swartz,  the  use 
of  the  generic  term  Dryopteris  is  necessitated  by 
the  rules  of  botanic  nomenclature.  The  synonyms 
for  the  male  fern  are  extraordinarily  numerous. 
The  following  have  been  among  those  occasionally 
used:  Aspidium  Filix-mas,  of  many  authors; 
Polypodium  Filix-mas  Linn.;  and  Polystichum 
Filix-mas  Roth. 

The  Male  Fern  is  very  widely  distributed,  oc- 
curring in  Greenland,  Europe,  Asia,  Northern 
Africa  and  in  some  of  the  Polynesian  Islands; 
in  the  Western  Hemisphere  it  is  found  in  the 
Rocky  Mountains  in  North  America  and  the 
Andes  Mountains  in  South  America.  It  has  a 
perennial,  oblique  rhizome,  from  which  numerous 
annual  fronds  arise,  forming  tufts  from  a  foot 
to  four  feet  in  height.  The  stipe,  or  petiole,  and 
midrib  are  thickly  beset  with  brown,  tough,  trans- 
parent scales;  the  frond  itself  is  ovate-oblong  in 
outline,  the  pinnae  being  linear-lanceolate,  taper- 
ing from  base  to  apex.  The  fructification  is  in 
small  dots  on  the  back  of  each  lobe,  occurring 
close  to  the  midvein. 

The  leather  wood  jern  or  marginal  fern,  Dry- 
opteris marginalis  (L.)  Asa  Gray  (Aspidium 
marginale  Sw. ;  Polypodium  marginale  L.),  differs 
from  the  preceding  by  having  the  sori  (fruit 
bodies)  on  the  margin  of  the  leaves  instead  of 
near  the  midrib.  It  is  found  in  rocky  woods  and 
on  banks  in  eastern  North  America  from  Nova 
Scotia  to  Alabama.  Wilson  (Thesis,  Massachusetts 
Coll.  Pharm.,  1925)  found  the  oleoresin  from  the 
marginal  fern  to  yield  from  22  to  24  per  cent  of 
crude  filicin. 

It  is  probable  that  all  of  the  species  of  this 
genus  possess  more  or  less  anthelmintic  prop- 
erties. According  to  Rosendahl  (Pharm.  J.,  1911, 
87,  35)  the  Dryopteris  dilatata  is  indeed  four 
times  as  active  a  poison  to  the  tapeworm  as  the 
true  aspidium.  D.  spinulosa  Kuntze  is  often  found 
mixed  with  the  male  fern  in  Germany.  Lauren 
(Apoth.-Ztg.,  1903)  stated  that  this  species  is  an 
active  taeniacide  less  liable  to  cause  disagreeable 
sensations.  The  D.  rigida  Underw.  of  the  Pacific 
coast  is  used  in  the  western  U.  S.  as  a  vermifuge. 

The  Athyrium  Filix- jemina  (L.)  Bernh.,  or 
Lady  Fern,  is  also  popularly  ascribed  with  taenia- 
fuge  properties.  Kiirsten  (Pharm.  J.,  1891)  found 
in  it  pannic  acid  (or  pannol)  which  is  closely  re- 
lated to  filicic  acid;  it  differs  in  being  soluble  in 
strong  alcohol  and  in  not  yielding  isobutyric  acid 
on  hydrolysis.  Under  the  name  of  inkomankomo  or 
uncomocomo,  the  rhizome  of  Aspidium  athamanti- 
cum  (Hook.)  Kuntze,  has  long  been  used  by  the 
South  African  Kaffirs,  and  has  entered  European 
commerce  as  pannum  (Rhizoma  Pannce).  In  it 
Heffter  (Arch.  exp.  Path.  Pharm.,  1897,  38,  458) 


122  Aspidium 


Part  I 


found  three  well  characterized  and  crystallized 
principles:  flavopannin,  albopannin  and  pannol 
(pannic  acid  of  Kiirsten).  Both  flavopannin  and 
albopannin  are  powerful  muscle  poisons,  directly 
affecting  the  heart. 

Extracts  of  male  fern  undergo  some  chemical 
change  on  standing  which  leads  to  a  loss  of  filicin 
content  (Goris  and  Metin,  Bull.  sc.  Pharmacol., 
May,  1924).  According  to  Pedretti  {them.  Abs., 
1931,  25,  4658)  physiologically  active  amorphous 
filicic  acid  is  changed  into  a  crystalline  inert  form. 

The  rhizomes  of  other  species  of  fern  are  fre- 
quently substituted  for  the  official,  and  in  the 
dried  state  it  is  difficult  to  distinguish  them.  The 
varying  results  reported  by  physicians,  when  using 
this  drug,  are  no  doubt  due  to  use  of  spurious 
male  fern,  or  old  rhizomes  and  stipe  bases  which 
are  devoid  of  any  greenish  color  internally. 

In  collecting  male  fern,  all  the  black,  discolored 
portions  should  be  cut  away,  the  fibers  and  scales 
separated,  and  only  the  sound  green  parts  pre- 
served. Most  of  the  drug  is  gathered  in  this  coun- 
try, especially  in  New  Hampshire.  Some  supplies 
of  Male  Fern  from  Dryopteris  Filix-m